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Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0007640 Sorsby fundus dystrophy

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Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant with penetrance reported as complete, and variable expressivity in age of onset and fundus appearance. A historically proposed autosomal recessive form rests on one consanguineous Finnish family; the same family was later shown to carry a heterozygous Gly166Cys TIMP3 variant in all affected members, which the authors read as dominant inheritance, and the ClinGen Retina GCEP records the recessive proposal as refuted. The MONDO descendant MONDO:0009918, the recessive pseudoinflammatory form (OMIM 264420), is therefore not curated as a subtype of this entry.

Autosomal dominant inheritance Penetrance: COMPLETE Expressivity: VARIABLE

Show evidence (5 references)

PMID:36197222 SUPPORT REVIEW SYNTHESIS Other

"Sorsby fundus dystrophy (SFD) is a rare autosomal dominant disorder with complete penetrance affecting the macula."

A narrative review states autosomal dominant inheritance with complete penetrance.

PMID:8981947 SUPPORT Human clinical

"We identified a novel heterozygous Gly166Cys mutation in TIMP3 in all affected individuals and provide strong evidence for an autosomal dominant inheritance of the SFD phenotype in this family."

Reinvestigation of the family that defined the recessive concept found a heterozygous variant segregating with disease.

PMID:8981947 SUPPORT Human clinical

"Considering all available data, we suggest that SFD is a genetically homogeneous, autosomal dominant condition."

The authors' conclusion against a recessive mode of inheritance, which is the basis for leaving the recessive MONDO descendant out.

+ 2 more references

?

Discussions and Knowledge Gaps

3

Is dimerization of mutant TIMP-3 the step that produces its accumulation in Bruch's membrane, or is accumulation of monomeric mutant protein sufficient?

KNOWLEDGE GAP OPEN sfd_dimerization_vs_monomer_accumulation

Attached to

pathophysiology#Aberrant TIMP-3 Disulfide Bonding and Multimerization pathophysiology#Resistance of Mutant TIMP-3 to Extracellular Matrix Turnover

Expression studies in RPE-derived and other cell lines report disulfide-bonded dimers and multimers for every variant tested and tie turnover resistance to intermolecular bonding, which is the model the pathograph follows. Patient-derived iPSC-RPE instead accumulated TIMP3 monomers basolaterally and showed dimers in control cultures too, and for the N-terminal Ser38Cys allele the reported defect is intramolecular bonding with no confirmed dimerization. The two kinds of system differ in whether the protein is overexpressed, so the disagreement bears on whether dimerization is mechanism or a consequence of expression level.

Show evidence (2 references)

PMID:37013036 SUPPORT In vitro / ex vivo

"In summary, our data support the hypothesis that all SFD-mutated forms of TIMP3 result in dimerization/multimerization of the protein which in turn significantly impairs its ability to inhibit the proangiogenic growth factor receptor VEGFR2."

One side of the disagreement, from transfected RPE-derived cells expressing each reported variant.

PMID:32666594 REFUTE In vitro / ex vivo

"TIMP3 dimers were observed in both SFD and control hiPSC-RPE, suggesting that mutant TIMP3 dimerisation does not drive SFD pathology."

The other side, from patient-derived RPE expressing the variant at endogenous level.

Does any current model reproduce the loss of central vision that defines this disease in people?

HUMAN MODEL MISMATCH OPEN sfd_no_model_reproduces_vision_loss

Attached to

animal_models#Mouse experimental_models#Patient-derived SFD iPSC-RPE phenotypes#Progressive central vision loss

The Timp3 knock-in mouse reproduces the Bruch's membrane and RPE changes but keeps normal retinal function on electrodiagnostic recording throughout life, needs laser injury before neovascular leakage appears, and has no macula. Patient-derived iPSC-RPE reproduces matrix accumulation and deposits but has no choroid, no photoreceptors and no neovascular compartment. So the structural half of the disease is modelled and the functional endpoint is not, which is what a preventive trial would need.

Show evidence (2 references)

PMID:12147610 SUPPORT Model organism

"Long-term electrodiagnostic recordings indicated normal retinal function throughout life."

The knock-in mouse carries the structural lesion without any functional deficit, which is the mismatch this gap records.

PMID:34929159 SUPPORT In vitro / ex vivo

"Our findings suggest that elements of SFD pathology can be demonstrated in culture which may lead to insights into disease mechanisms."

The cell model's own authors claim elements of the pathology, not the clinical endpoint.

Do SFD TIMP3 alleles other than Ser156Cys lose the ability to inhibit ADAM17, and does a resulting rise in tumour necrosis factor alpha signalling contribute to the disease, as the response of one patient to adalimumab would suggest?

KNOWLEDGE GAP OPEN sfd_adam17_tnf_arm

Attached to

treatments#Systemic anti-TNF-alpha therapy (single case report)

TIMP-3 is the only TIMP that inhibits ADAM17, the sheddase of tumour necrosis factor alpha, so a variant that lost that inhibition could raise local tumour necrosis factor alpha. One patient with the Ser181Cys allele responded to adalimumab, which is the clinical hint. But the one allele measured, Ser156Cys, inhibits ADAM17 as well as wild-type TIMP-3 does, and the other SFD alleles, including the patient's, have not been profiled. So the inflammatory arm is neither supported nor excluded for the disease, and no mechanism node is drawn for it until an allele relevant to a patient is tested.

Proposed experiments

ADAM17 and TNF-alpha shedding across an SFD TIMP3 allele panel

sfd_adam17_inhibition_allele_panel

Express a panel of SFD TIMP3 alleles, including Ser181Cys and other C-terminal cysteine variants, in a cell system and measure ADAM17 inhibitory activity and ADAM17-mediated shedding of tumour necrosis factor alpha, against wild-type TIMP-3 and the already-profiled Ser156Cys as references.

Would support

treatments#Systemic anti-TNF-alpha therapy (single case report)

Supporting outcome

One or more patient-relevant SFD alleles show reduced ADAM17 inhibition and increased tumour necrosis factor alpha shedding relative to wild-type, which would make raised ocular tumour necrosis factor alpha a plausible arm and the adalimumab response mechanistically coherent.

Refuting outcome

SFD alleles retain wild-type ADAM17 inhibition, which would leave the adalimumab response unexplained by this mechanism.

Show evidence (2 references)

PMID:34376817 SUPPORT Human clinical

"Direct inhibition of TNFα action by adalimumab offers a molecularly targeted approach to the disease pathophysiology and merits increased study."

The single-patient response and the authors' call for further study are the clinical basis of the open question.

PMID:38601018 SUPPORT REVIEW SYNTHESIS Other

"The ability of other SFD TIMP-3 mutants to inhibit these and other relevant ADAMs and ADAMTSs has not been profiled, so additional work in this area is needed."

States that the question is open for the alleles that matter clinically, which is what keeps this a gap rather than a settled negative.

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Pathophysiology

14

TIMP3 Cysteine-Altering Variant

A heterozygous TIMP3 variant, in most reported cases a missense change in exon 5 affecting the C-terminal domain of the protein, adds or removes a cysteine residue and so disturbs the arrangement of the conserved cysteines and disulfide bonds that hold the tertiary structure together. A minority of reported alleles do not alter a cysteine (for example His158Arg) or lie outside exon 5 (Ser38Cys in exon 1), and one nonsense allele leaves an unpaired cysteine. Mutant protein continues to be expressed and to localize to the extracellular matrix, so the primary consequence is an altered protein rather than its absence.

retinal pigment epithelial cell CL:0002586

TIMP3 hgnc:11822

Genetic context allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS

TIMP-3 metalloendopeptidase inhibitor activity GO:0008191 ⚠ ABNORMAL

Downstream

Aberrant TIMP-3 Disulfide Bonding and Multimerization The unpaired cysteine introduced by the variant forms intermolecular or aberrant intramolecular disulfide bonds, so the mutant protein dimerizes or multimerizes.

Increased MMP2 Activity and bFGF Release Mutant TIMP-3 restrains metalloproteinases less well in vivo, raising MMP2 activity and the level of basic fibroblast growth factor.

RPE Glucose and Glutamine Metabolic Dysregulation Mutant TIMP3 is accompanied by a metabolism-weighted change in the RPE proteome and by raised glycolytic flux; how the extracellular protein produces the intracellular metabolic change is not established.

Increased RPE Susceptibility to Oxidative Stress Mutant Timp3 is associated with a pro-oxidant state in the RPE; the steps between the altered protein and that state are not established.

Show evidence (5 references)

PMID:7894485 SUPPORT Human clinical

"We have now identified point mutations in the TIMP3 gene in affected members of two SFD pedigrees."

The gene discovery study identified TIMP3 point mutations in affected members of two SFD families.

PMID:7894485 SUPPORT Human clinical

"These mutations are predicted to disrupt the tertiary structure and thus the functional properties of the mature protein."

States the predicted structural consequence of the variants on the mature protein.

PMID:28847738 SUPPORT REVIEW SYNTHESIS Other

"Most SFD-associated TIMP3 variants involve the gain or loss of a cysteine residue."

A review of the reported variant set states that most alter a cysteine residue.

+ 2 more references

Aberrant TIMP-3 Disulfide Bonding and Multimerization

Mutant TIMP-3 forms disulfide-bonded dimers and higher-molecular-weight complexes in the extracellular matrix. The complexes retain the protein's metalloproteinase-inhibitory activity and its matrix localization in most assays, so the molecular lesion is an altered quaternary state rather than a dead enzyme inhibitor. Two separable consequences follow: the complexes resist turnover, and they inhibit VEGFR2 less well.

TIMP-3 multimer formation GO:0051260 ↑ INCREASED

aberrant TIMP-3 protein dimerization GO:0046983 ⚠ ABNORMAL

Downstream

Resistance of Mutant TIMP-3 to Extracellular Matrix Turnover Intermolecular disulfide bonding is what makes the mutant proteins resistant to turnover from the matrix.

Impaired TIMP-3 Inhibition of VEGFR2 Dimerization about the C-terminal domain, the part of the molecule that is necessary and sufficient for receptor inhibition, impairs inhibition of VEGFR2.

Show evidence (5 references)

PMID:37013036 SUPPORT In vitro / ex vivo

"In summary, our data support the hypothesis that all SFD-mutated forms of TIMP3 result in dimerization/multimerization of the protein which in turn significantly impairs its ability to inhibit the proangiogenic growth factor receptor VEGFR2."

Expression of the full reported variant set in RPE-derived cells supports dimerization or multimerization as a common molecular phenotype.

PMID:9642234 SUPPORT In vitro / ex vivo

"This gave rise to an additional 48-kDa species (possibly a TIMP-3 dimer) that retained its ability to inhibit MMPs and localize to the ECM."

The Ser181Cys protein forms an extra species of about twice the monomer mass while keeping inhibitory activity and matrix binding.

PMID:11827795 SUPPORT In vitro / ex vivo

"Two of the mutants (Ser156Cys and Ser181Cys) showed a marked propensity to form multiple higher molecular-weight complexes that retained TIMP activity on reverse zymography."

Documents higher-molecular-weight complexes that keep inhibitory activity, for two of the four mutants assayed.

+ 2 more references

Resistance of Mutant TIMP-3 to Extracellular Matrix Turnover

Disulfide-linked mutant TIMP-3 is cleared from the extracellular matrix more slowly than wild-type protein by retinal pigment epithelial cells. Transcript levels are not raised in affected eyes, so the accumulation is post-translational rather than an increase in expression. The process is bound as protein catabolism of TIMP-3, decreased, because the defect is the clearance of one protein from the matrix, not breakdown of the matrix as a whole.

retinal pigment epithelial cell CL:0002586

TIMP-3 turnover from the extracellular matrix GO:0030163 ↓ DECREASED

extracellular matrix GO:0031012

Experimental models

Patient-derived SFD iPSC-RPE IPSC DERIVED MODEL Patient RPE accumulates TIMP3 basolaterally with no change in gene expression, which is the post-translational accumulation this node describes. The same study did not find mutant-specific dimerization.

Downstream

TIMP-3 Accumulation in Bruch's Membrane Because TIMP-3 is secreted by the RPE into Bruch's membrane, protein that is not turned over accumulates there.

Show evidence (3 references)

PMID:16223891 SUPPORT In vitro / ex vivo

"These data show that increased deposition of active TIMP-3, rather than dysregulation of metalloproteinase inhibition, is likely to be the primary, initiating event in SFD."

The authors' conclusion from expressing the mutants in human RPE cells, that deposition of still-active protein is the initiating event.

PMID:14597066 SUPPORT Human clinical

"There is a reduction of mRNA expression of MMP-2 and TIMP-3 in the Sorsby retinal pigment epithelium cells."

In situ hybridization in an SFD donor eye shows no transcriptional overexpression, so accumulation is not driven by increased synthesis.

PMID:9642234 SUPPORT In vitro / ex vivo

"These data favor the hypothesis that the TIMP-3 mutations seen in Sorsby's fundus dystrophy contribute to disease progression by accumulation of mutant protein rather than by the loss of functional TIMP-3."

Supports accumulation rather than loss of function as the route from the variant to disease.

TIMP-3 Accumulation in Bruch's Membrane

TIMP-3 is made by the retinal pigment epithelium and is normally a component of Bruch's membrane, where it regulates the thickness of that matrix by inhibiting matrix metalloproteinases. In SFD eyes the thickened membrane and the sub-RPE deposits label strongly for TIMP-3, and the protein is increased in the extracellular matrix of patient-derived RPE, so the mutant protein accumulates in the compartment where the wild-type protein normally works.

retinal pigment epithelial cell CL:0002586

basement membrane GO:0005604

Bruch's membrane UBERON:0003957

Experimental models

Patient-derived SFD iPSC-RPE IPSC DERIVED MODEL Reproduces the accumulation of TIMP3 in the matrix beneath the RPE and the sub-RPE deposit.

Animal models

Timp3 S156C knock-in mouse Mouse recapitulates Reproduces the accumulation of Timp3 in Bruch's membrane and the membrane abnormality.

Downstream

Bruch's Membrane Thickening and Sub-RPE Deposit Formation Sequestration of excess TIMP-3 and matrix in Bruch's membrane thickens it and builds confluent deposits beneath the RPE basement membrane.

Show evidence (6 references)

PMID:9006347 SUPPORT Human clinical

"The results indicate that TIMP-3 is an extracellular matrix component of Bruch's membrane."

Establishes the normal location of the protein, which is the compartment this node is about.

PMID:8759363 SUPPORT Model organism

"TIMP-3 mRNA expression was detected strongly in the retinal pigment epithelium (RPE) and to a minor extent in the ciliary epithelium, but not at any other site within the eye."

In situ hybridization in mouse eyes identifies the RPE as the ocular source of the protein.

PMID:9924344 SUPPORT Human clinical

"In the SFD eyes, the thickened Bruch's membrane was strongly TIMP-3 positive except where RPE cells had degenerated."

Donor eyes with a confirmed TIMP3 variant show TIMP-3 accumulation in the thickened membrane.

+ 3 more references

Bruch's Membrane Thickening and Sub-RPE Deposit Formation

Confluent amorphous deposits, about 20 to 30 micrometres thick, lie between the RPE basement membrane and the inner collagenous layer of Bruch's membrane, and the membrane itself is thickened; the deposits contain collagens, elastin, glycosaminoglycans, lipids and calcium, and the elastic layer of Bruch's membrane is morphologically altered. Unlike age-related macular degeneration the thickening is diffuse rather than confined to the macula, and it is detectable by optical coherence tomography in carriers who have no symptoms. The deposits are the structural lesion that underlies the drusen-like fundus lesions, the transport barrier and the choriocapillaris changes.

Bruch's membrane extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Bruch's membrane UBERON:0003957

Downstream

Impaired Transport Across Bruch's Membrane The thickened, deposit-laden membrane is a diffusion barrier between the choroidal blood supply and the outer retina.

Choriocapillaris Flow Impairment Choriocapillaris flow deficits accompany the sub-RPE deposits but extend beyond them, so the deposit does not simply mask the vessels and the intermediate steps are undefined.

Drusen-like sub-RPE deposits The sub-RPE deposits are what ophthalmoscopy sees as drusen-like lesions.

Yellow/white macular and retinal lesions

Reticular pseudodrusen Reticular pseudodrusen are subretinal rather than sub-RPE, and their association with SFD is read as implicating Bruch's membrane or its interface with the RPE rather than as a direct consequence of the deposit.

Abnormal indocyanine green angiography

Show evidence (5 references)

PMID:32828705 SUPPORT BACKGROUND Human clinical

"The predominant histopathological feature in the eyes of patients with SFD are confluent, 20–30 μm thick, amorphous deposits found between the basement membrane of the retinal pigment epithelium (RPE) and the inner collagenous layer of Bruch's membrane."

Gives the location and thickness of the defining deposit.

PMID:10711711 SUPPORT Human clinical

"Both deposits contained collagens, elastin, glycosaminoglycans, lipids, and calcium."

Gives the composition of the sub-RPE deposit in a donor eye with a confirmed variant.

PMID:10711711 SUPPORT Human clinical

"Electron microscopy revealed a morphologically altered elastic layer of the Bruch's membrane."

Documents the structural change in the membrane itself.

+ 2 more references

Impaired Transport Across Bruch's Membrane

The thickened membrane and its deposits reduce metabolic exchange between the choroid and the outer retina. The hypothesis tested clinically was that the barrier locally deprives photoreceptors of vitamin A, and the reversal of night blindness by oral vitamin A within a week supports it.

retinol transport to the photoreceptors GO:0034633 ↓ DECREASED

Bruch's membrane UBERON:0003957

Downstream

Photoreceptor Vitamin A Deprivation Restoring the supply by high oral doses abolishes the functional deficit, which is the clinical evidence that the barrier deprives photoreceptors of vitamin A.

Show evidence (1 reference)

PMID:7550309 SUPPORT Human clinical

"In a SFD family with a novel TIMP3 point mutation, we tested a hypothesis that their night blindness is due to a chronic deprivation of vitamin A at the level of the photoreceptors caused by a thickened membrane barrier between the photoreceptor layer and its blood supply."

States the barrier hypothesis that the same study then tested by supplementation.

Photoreceptor Vitamin A Deprivation

Local deficiency of vitamin A at the photoreceptors slows rhodopsin regeneration and so delays rod-mediated dark adaptation. Scotopic thresholds are elevated and the rod portion of the dark adaptation curve is prolonged in retinal regions carrying the deposit, while ophthalmoscopically normal regions are affected minimally; rod-mediated dark adaptation can nonetheless be slowed before any change is visible on multimodal imaging.

retinal rod cell CL:0000604

dark adaptation GO:1990603 ↓ DECREASED retinoid metabolic process GO:0001523 ⚠ ABNORMAL

Downstream

Nyctalopia Slowed rod dark adaptation presents as night blindness.

Show evidence (4 references)

PMID:1559761 SUPPORT Human clinical

"In retinal regions with the yellow deposit, scotopic thresholds were elevated, the rod-cone break was delayed or indistinct, the time courses for the rod portion of the dark adaptation curve was prolonged, and rhodopsin regeneration was slow in the one patient in whom measurements were made."

Measures the rod functional deficit and its co-location with the deposit.

PMID:1559761 SUPPORT Human clinical

"In regions of ophthalmoscopically normal retina, dark adaptation was affected minimally, and in one patient, rhodopsin was regenerated at a normal rate."

The regional correspondence between deposit and deficit supports a local rather than systemic cause.

PMID:34352251 SUPPORT Human clinical

"Patients with SFD exhibit severely impaired scotopic visual function even in the absence of funduscopic alterations on multimodal imaging."

A prospective study of 16 patients and 20 controls found severely impaired rod-driven function, present before any fundus change.

+ 1 more reference

Impaired TIMP-3 Inhibition of VEGFR2

Wild-type TIMP-3 blocks VEGF binding to VEGF receptor-2 and so inhibits angiogenesis, a function of the C-terminal domain and independent of its metalloproteinase inhibition. Dimerized mutant protein inhibits the receptor much less well. For the Ser156Cys allele, endothelial cells expressing the mutant protein bind more VEGF and show increased VEGF-dependent migration and tube formation, with more membrane-associated VEGFR-2 in mutant mouse endothelium and in human SFD eyes.

endothelial cell CL:0000115

vascular endothelial growth factor receptor-2 signaling GO:0036324 ↑ INCREASED

Animal models

Timp3 S156C knock-in mouse Mouse recapitulates Mutant mouse endothelium carries more membrane-associated VEGFR-2, the same change reported in human SFD eyes.

Downstream

Choroidal Neovascular Membrane Formation Loss of restraint on VEGFR2 is the proposed route to the neovascular membranes that characterize the disease.

Show evidence (4 references)

PMID:12652295 SUPPORT In vitro / ex vivo

"TIMP3 blocks the binding of VEGF to VEGF receptor-2 and inhibits downstream signaling and angiogenesis."

Establishes the wild-type function whose impairment this node describes.

PMID:12652295 SUPPORT In vitro / ex vivo

"This property seems to be independent of its MMP-inhibitory activity, indicating a new function for this molecule."

Supports treating the VEGFR2 arm as separable from the metalloproteinase-inhibition arm.

PMID:19478078 SUPPORT In vitro / ex vivo

"Here we report that expression of S156C TIMP-3 mutation in endothelial cells results in an abnormal localization of the protein, increased glycosylation, decreased matrix metalloproteinase inhibitory activity, and increased vascular endothelial growth factor (VEGF) binding with a consequent..."

Shows the pro-angiogenic consequence of the mutant protein in endothelial cells.

+ 1 more reference

Increased MMP2 Activity and bFGF Release

In the Timp3 S179C knock-in mouse, reduced metalloproteinase inhibition raises MMP2 activity and basic fibroblast growth factor levels, mutant RPE cells secrete more bFGF, and conditioned medium from them drives endothelial angiogenesis. This is a second, VEGF-independent route to neovascularization; the mouse work is the principal source, and the equivalent human measurement has not been reported.

retinal pigment epithelial cell CL:0002586

fibroblast growth factor receptor signaling pathway GO:0008543 ↑ INCREASED

Downstream

Choroidal Neovascular Membrane Formation The authors propose an FGFR-1-dependent route from the mutant protein to neovascularization, alongside the VEGFR2 route.

Show evidence (1 reference)

PMID:31757977 SUPPORT In vitro / ex vivo

"S179C mutant-TIMP3 in retinal pigment epithelial (RPE) cells showed increased secretion of bFGF and conditioned medium from these cells induced increased angiogenesis in endothelial cells."

Mutant RPE cells secrete more bFGF and their medium is pro-angiogenic.

Choroidal Neovascular Membrane Formation

New vessels grow from the choroid through Bruch's membrane under the retina, with subretinal hemorrhage and exudation, and organize into a disciform macular scar. The median age at onset in the first eye was 46.1 years in a 42-patient Ser181Cys cohort, and the second eye followed on average 4.5 years later. Polypoidal choroidal neovascularization also occurs. This is the main cause of blindness in the disease, and the lesion that anti-VEGF therapy addresses.

endothelial cell CL:0000115

choroidal angiogenesis GO:0001525 ↑ INCREASED

capillary layer of choroid UBERON:0005336

Animal models

Timp3 S156C knock-in mouse Mouse partially recapitulates Neovascular leakage is accentuated in mutant mice, but only after laser injury rather than spontaneously.

Downstream

Choroidal neovascularization The neovascular membrane is what is seen and treated clinically as choroidal neovascularization.

Subretinal hemorrhage

Disciform macular scar The neovascular lesion organizes into subretinal fibrosis and a disciform scar.

Polypoidal choroidal vasculopathy

Metamorphopsia

Progressive central vision loss Vision falls to 20/200 or below within a couple of years of neovascular onset in untreated eyes.

Show evidence (2 references)

PMID:18501328 SUPPORT Human clinical

"The main cause of blindness resulting from this dystrophy is CNV."

A 42-patient cohort identifies neovascularization as the main cause of blindness.

PMID:18501328 SUPPORT Human clinical

"The median age at onset of CNV in the first eye was 46.1 years and in the second eye was 50.3 years."

Gives the age of onset in each eye in that cohort.

Choriocapillaris Flow Impairment

Flow signal deficits in the choriocapillaris are pronounced in early disease, extend beyond the areas of sub-RPE deposit, and track with thinning of the overlying photoreceptor layers. Choroidal thickness is a structural correlate of the deficit, whereas the thickness of the RPE-drusen complex is not.

capillary layer of choroid UBERON:0005336

Downstream

Photoreceptor and RPE Degeneration Flow deficit density is associated with thinning of the overlying photoreceptor layers; the association is cross-sectional, so the direction of causation is not established by it.

Show evidence (2 references)

PMID:34844251 SUPPORT Human clinical

"Patients with early SFD exhibit pronounced abnormalities of CC flow signal on OCTA, which are not limited to areas of sub-RPE deposits seen on OCT imaging."

A case-control study of 18 eyes finds pronounced choriocapillaris flow abnormality in early disease.

PMID:34844251 SUPPORT Human clinical

"Thus, analysis of the CC flow may enable clinical trials at earlier disease stages in SFD."

The authors read the flow deficit as an early-stage disease measure, which is what places this node upstream of degeneration.

RPE Glucose and Glutamine Metabolic Dysregulation

RPE carrying a disease-associated TIMP3 variant uses more glucose and runs a higher glycolytic flux, shown by isotopic tracing in mutant ARPE-19 cells and in patient-derived iPSC-RPE, with altered malic enzyme activity on glutamine tracing. Because the RPE supplies glucose to the outer retina, the authors read this as a contributor to degeneration rather than as a bystander finding; it is a recent result and the step from metabolic change to cell loss is not yet demonstrated in this disease.

retinal pigment epithelial cell CL:0002586

glycolysis in the retinal pigment epithelium GO:0006096 ↑ INCREASED glutamine metabolism GO:0006541 ↕ DYSREGULATED

Show evidence (3 references)

PMID:39047907 SUPPORT In vitro / ex vivo

"Stable isotope tracing experiments with ... glucose demonstrated enhanced glucose utilization and glycolytic activity in S179C TIMP3 APRE-19 cells."

Isotopic tracing measures the raised glycolytic flux in mutant RPE-derived cells.

PMID:39047907 SUPPORT In vitro / ex vivo

"Additionally, ... glutamine tracing found evidence of altered malic enzyme activity."

Glutamine tracing in patient-derived RPE shows the second metabolic change this node records.

PMID:39047907 SUPPORT In vitro / ex vivo

"This study provides important information on the dysregulation of RPE glucose metabolism in SFD and implicates a potential commonality with other retinal degenerative diseases, emphasizing RPE cellular metabolism as a therapeutic target."

The authors' own statement of what the finding establishes, which stops short of a demonstrated route to cell loss.

Increased RPE Susceptibility to Oxidative Stress

RPE carrying a disease-associated Timp3 variant is more vulnerable to oxidative insult. Antioxidant genes are raised at baseline in mutant mouse RPE, and doses of sodium iodate that do not affect wild-type mice degenerate the mutant RPE and photoreceptors. Patient-derived RPE has lower reduced glutathione and is likewise more vulnerable. This is a second route to RPE loss, independent of neovascularization.

retinal pigment epithelial cell CL:0002586

cellular response to oxidative stress GO:0034599 ⚠ ABNORMAL

Animal models

Timp3 S156C knock-in mouse Mouse recapitulates Mutant RPE carries a baseline antioxidant response and degenerates at oxidative doses that spare wild-type tissue.

Downstream

Photoreceptor and RPE Degeneration Under low-dose oxidative insult the mutant RPE and photoreceptors degenerate where wild-type tissue does not.

Show evidence (1 reference)

PMID:34929159 SUPPORT In vitro / ex vivo

"Finally, SFD RPE cells have decreased intracellular reduced glutathione and were found to be more vulnerable to oxidative stress."

Patient-derived RPE is depleted of reduced glutathione and more vulnerable to oxidative stress.

Photoreceptor and RPE Degeneration

Progressive atrophy of the retinal pigment epithelium, the photoreceptors and the choriocapillaris spreads from the posterior pole toward the periphery, giving geographic atrophy and finally widespread chorioretinal atrophy with fibrosis and choroidal thinning. Severe vision loss can occur by this route without any neovascular membrane.

retinal pigment epithelial cell CL:0002586 photoreceptor cell CL:0000210

macula UBERON:0000054

Downstream

Chorioretinal atrophy

Macular geographic atrophy Rapidly progressive geographic atrophy is part of the ocular phenotype.

Choriocapillaris atrophy

Central scotoma

Progressive central vision loss Atrophy alone can take vision to a severe level without a neovascular membrane.

Show evidence (2 references)

PMID:25766588 SUPPORT Human clinical

"Late disease manifestations were uniform with widespread chorioretinal atrophy, fibrosis, and choroidal thinning."

Describes the end-stage atrophic picture across three families.

PMID:7920634 SUPPORT BACKGROUND Human clinical

"Patients lose central vision from subretinal neovascularization and atrophy of the choriocapillaris, pigment epithelium and retina."

Names both routes to central vision loss, the neovascular and the atrophic.

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Pathograph

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Phenotypes

16

Blood 1

Subretinal hemorrhage HP:0025243

Show evidence (2 references)

CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z SUPPORT Other

"affected individuals present with a range of clinical features including yellow/white lesions of the retina, nyctalopia, progressive loss of central vision, disciform macular scar, central scotoma, retinal exudate, subretinal hemorrhage, atrophy of the retina / choriocapillaris / retinal pigment..."

The ClinGen evidence summary lists subretinal hemorrhage among the clinical features of the disease.

PMID:23099917 SUPPORT Human clinical

"in October 2007, an extensive macular hemorrhage developed with vision dropping to 6/60"

A case in which macular hemorrhage from the neovascular lesion dropped acuity to 6/60.

Eye 14

Nyctalopia FREQUENT HP:0000662

Show evidence (3 references)

PMID:30668888 SUPPORT BACKGROUND Human clinical

"Typical manifestations include night blindness, scotoma, and metamorphopsia with subsequent reduced central, detailed vision and color vision problems"

Names night blindness among the typical manifestations of the disease.

ORPHA:59181 SUPPORT Other

"HP:0000662 | Nyctalopia | Frequent (79-30%)"

Orphanet's HPO annotation records nyctalopia as frequent in this disease.

PMID:25766588 SUPPORT Human clinical

"The p.Tyr174Cys mutation carriers had first symptoms at approximately the third decade with dark adaptation problems and visual field defects."

In one family dark adaptation problems were the presenting symptom, in the third decade.

Drusen-like sub-RPE deposits VERY_FREQUENT HP:0011510

Show evidence (3 references)

PMID:28847738 SUPPORT REVIEW SYNTHESIS Other

"ophthalmoscopy reveals accumulation of protein/lipid deposits under the retinal pigment epithelium (RPE), referred to as drusen, in the eyes of patients with SFD"

States the clinical finding and its sub-RPE location.

PMID:30668888 SUPPORT BACKGROUND Human clinical

"The disease is characterized by thickening of the Bruch membrane, chorioretinal atrophy, and multiple drusen‐like deposits throughout the entire fundus."

Gives the fundus-wide distribution of the deposits.

ORPHA:59181 SUPPORT Other

"HP:0031528 | Subretinal deposits | Very frequent (99-80%)"

Orphanet records deposits as very frequent in this disease.

Yellow/white macular and retinal lesions VERY_FREQUENT Yellow/white macular lesion HP:0030500

Show evidence (2 references)

PMID:2695876 SUPPORT Human clinical

"in the first and most common, white to yellow fundus spots (which are not drusen) accompany a disciform macular degeneration"

Describes the yellow/white fundus lesions in a seven-generation pedigree.

ORPHA:59181 SUPPORT Other

"HP:0030500 | Yellow/white lesions of the macula | Very frequent (99-80%)"

Orphanet records the lesions as very frequent.

Reticular pseudodrusen Subretinal deposits HP:0031528

Show evidence (2 references)

PMID:26077580 SUPPORT Human clinical

"Reticular pseudodrusen were identified frequently in SFD patients in the sixth decade of life (5 of 7 [71%]) and were absent in younger (n = 3) or older (n = 6) patients."

Gives the prevalence and age dependence in 16 patients from four families.

PMID:26077580 SUPPORT Human clinical

"They appeared as subretinal deposits on SD OCT imaging."

Locates the lesions above the RPE, which is what the bound term asserts.

Abnormal indocyanine green angiography HP:0030605

Show evidence (2 references)

PMID:25766588 SUPPORT Human clinical

"Three asymptomatic young carriers of a TIMP3 mutation with otherwise normal findings on funduscopy and retinal imaging showed a characteristically reduced fluorescence on late-phase ICG-A images."

Documents the sign in asymptomatic carriers with otherwise normal imaging.

PMID:25766588 SUPPORT Human clinical

"This phenotypic sign was more pronounced and widespread in later disease stages."

The sign becomes more marked with disease stage.

Choroidal neovascularization FREQUENT HP:0011506

Show evidence (3 references)

PMID:18501328 SUPPORT Human clinical

"The mean interval between the development of CNV in the first and second eye was 4.5 years."

Gives the interval between eyes in a 42-patient cohort.

ORPHA:59181 SUPPORT Other

"HP:0011506 | Choroidal neovascularization | Frequent (79-30%)"

Orphanet records choroidal neovascularization as frequent.

PMID:27601084 SUPPORT BACKGROUND Human clinical

"SFD is characterized by bilateral deposition of yellow drusen-like material and extensive choroidal neovascularization (CNV) occurring between the third to fifth decades of life."

Gives the bilateral character and the decade of onset.

Polypoidal choroidal vasculopathy HP:0025569

Show evidence (1 reference)

PMID:25766588 SUPPORT Human clinical

"The ocular phenotype included drusen-like deposits, rapidly progressive geographic atrophy, choroidal neovascularization (CNV), and polypoidal choroidal neovascularization (PCV)."

Reports polypoidal lesions among the phenotype of three SFD families.

Disciform macular scar HP:0025094

Show evidence (2 references)

PMID:23099917 SUPPORT Human clinical

"The natural history of the condition involves early development of lesion fibrosis."

States that fibrosis of the neovascular lesion occurs early in the untreated course.

CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z SUPPORT Other

"disciform macular scar, central scotoma, retinal exudate"

The ClinGen evidence summary lists disciform macular scar among the clinical features.

Metamorphopsia HP:0012508

Show evidence (2 references)

PMID:25766588 SUPPORT Human clinical

"In families with p.Tyr177Cys and p.Tyr182Cys, metamorphopsia and/or decrease in visual acuity were the initial symptoms occurring at approximately the sixth decade of life."

Metamorphopsia was an initial symptom in two of the three studied families.

PMID:30668888 SUPPORT BACKGROUND Human clinical

"Typical manifestations include night blindness, scotoma, and metamorphopsia with subsequent reduced central, detailed vision and color vision problems"

Lists metamorphopsia among the typical manifestations.

Central scotoma FREQUENT HP:0000603

Show evidence (2 references)

CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z SUPPORT Other

"disciform macular scar, central scotoma, retinal exudate"

The ClinGen evidence summary lists central scotoma among the clinical features.

ORPHA:59181 SUPPORT INDIRECT Other

"HP:0001129 | Large central visual field defect | Frequent (79-30%)"

Orphanet records a large central visual field defect as frequent; the frequency band here is taken from that row, which names a broader class than the central scotoma the clinical sources describe.

Progressive central vision loss VERY_FREQUENT Progressive visual loss HP:0000529

Show evidence (3 references)

PMID:8981947 SUPPORT BACKGROUND Human clinical

"Sorsby fundus dystrophy (SFD) originally was characterized as an autosomal dominant disorder in which patients lose central vision during the 4th or 5th decade of life."

Gives the decade in which central vision is lost.

ORPHA:59181 SUPPORT Other

"HP:0000572 | Visual loss | Very frequent (99-80%)"

Orphanet records visual loss as very frequent.

PMID:34070857 SUPPORT BACKGROUND Human clinical

"leading to severe bilateral vision loss and blindness if left untreated"

States the untreated outcome, which is what the treatment section is measured against.

Chorioretinal atrophy HP:0000533

Show evidence (2 references)

PMID:2695876 SUPPORT Human clinical

"Atrophy of the retina, pigment epithelium, and choroid then slowly progresses toward the periphery."

Describes the spread of atrophy in a seven-generation pedigree.

PMID:25766588 SUPPORT Human clinical

"Late disease manifestations were uniform with widespread chorioretinal atrophy, fibrosis, and choroidal thinning."

Records widespread chorioretinal atrophy as the uniform late manifestation.

Macular geographic atrophy HP:0031609

Show evidence (2 references)

PMID:25766588 SUPPORT Human clinical

"The ocular phenotype included drusen-like deposits, rapidly progressive geographic atrophy, choroidal neovascularization (CNV), and polypoidal choroidal neovascularization (PCV)."

Lists rapidly progressive geographic atrophy in the phenotype of three families.

PMID:32828705 SUPPORT BACKGROUND Human clinical

"Patients with SFD present with pathophysiology similar to the more common Age-related Macular Degeneration (AMD) and loss of vision due to both choroidal neovascularization and geographic atrophy."

Names geographic atrophy as one of the two routes to vision loss.

Choriocapillaris atrophy FREQUENT HP:0030491

Show evidence (2 references)

ORPHA:59181 SUPPORT Other

"HP:0030491 | Choriocapillaris atrophy | Frequent (79-30%)"

Orphanet records choriocapillaris atrophy as frequent.

PMID:7920634 SUPPORT BACKGROUND Human clinical

"Patients lose central vision from subretinal neovascularization and atrophy of the choriocapillaris, pigment epithelium and retina."

Names choriocapillaris atrophy among the lesions that cost central vision.

Respiratory 1

Emphysema HP:0002097

Show evidence (2 references)

PMID:27601084 SUPPORT Human clinical

"In family 1, all SFD patients older than 50 (two generations) had also a severe emphysema, despite no history of smoking or asthma."

Reports severe emphysema co-segregating with the eye disease in one family.

CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z SUPPORT Other

"More recent reports have evaluated pulmonary function in affected individuals and found them to be normal, indicating that modifier genes and/or environmental exposures likely affect the penetrance of non-retinal features of Sorsby fundus dystrophy."

The ClinGen summary records that the pulmonary feature is not consistently present, which is why no frequency is recorded.

🧬

Genetic Associations

1

TIMP3 (Causative)

Gene: TIMP3 hgnc:11822 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (7 references)

PMID:7920634 SUPPORT Human clinical

"Recombinant chromosomes sublocalize the SFD gene to 22q13-qter between D22S275 and D22S274."

Linkage analysis placed the locus in the interval that contains TIMP3.

PMID:7894485 SUPPORT Human clinical

"We have now identified point mutations in the TIMP3 gene in affected members of two SFD pedigrees."

The original gene identification.

PMID:10854443 SUPPORT BACKGROUND Human clinical

"Five different mutations have previously been identified, all introducing an extra cysteine residue into exon 5 (which forms part of the C-terminal domain) of the TIMP-3 molecule"

Gives the exon and domain in which the early alleles sit and their shared cysteine effect.

+ 4 more references

Variants (5)

p.Ser181Cys Pathogenic

Gene: TIMP3 hgnc:11822 missense variant

The British Isles founder allele, found in 15 genealogically unrelated families and in emigrant families in Canada, the United States and South Africa. It is the allele of the 42-patient natural-history cohort and of the donor eyes used for the histopathology.

Also known as: S181C p.Ser204Cys

Show evidence (2 references)

PMID:8919688 SUPPORT Human clinical

"This haplotype analysis has refined the TIMP3 gene localization to a 1- to 3-cM interval between marker loci D22S273 and D22S281 and provides strong evidence for a single mutational event being responsible for the majority of SFD identified in the British Isles."

A single mutational event accounts for most British Isles disease.

PMID:18501328 SUPPORT Human clinical

"A cohort of 42 patients with the Ser181 Cys TIMP3 mutation were identified from the electronic database of genetic retinal diseases in Moorfields Eye Hospital."

Identifies the cohort whose natural history and treatment outcomes this entry cites as carrying this allele.

p.Ser156Cys Pathogenic

Gene: TIMP3 hgnc:11822 missense variant

Reported in a family with unusual clinical features, and the allele used for the knock-in mouse lines and for the endothelial and RPE cell work on VEGFR2 and bFGF. In cell assays it forms higher-molecular-weight complexes and shows reduced metalloproteinase inhibition with increased VEGF binding.

Also known as: S156C p.Ser179Cys

Show evidence (2 references)

PMID:12147610 SUPPORT Model organism

"To facilitate in vivo investigation of mutant TIMP3, the authors generated a knock-in mouse carrying a disease-related Ser156Cys mutation in the orthologous murine Timp3 gene."

Names the allele as disease-related and the basis of the knock-in model.

PMID:11827795 SUPPORT In vitro / ex vivo

"Two of the mutants (Ser156Cys and Ser181Cys) showed a marked propensity to form multiple higher molecular-weight complexes that retained TIMP activity on reverse zymography."

Documents the multimerization behaviour of this allele in cell culture.

p.Ser38Cys Pathogenic

Gene: TIMP3 hgnc:11822 missense variant

An exon 1 founder allele in Belgian and northern French families with late-onset disease. It is the clearest exception to the exon 5 rule: the reported mechanism is disruption of an established intramolecular disulfide bond and formation of a new one, rather than dimerization. The same allele was reported in a family with eye and lung disease.

Also known as: S38C c.113C>G

Show evidence (2 references)

PMID:30668888 SUPPORT Human clinical

"Haplotype reconstruction in three SFD families revealed that the identified c.113C>G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late-onset SFD phenotype."

Establishes the allele as a founder mutation with a late-onset phenotype.

PMID:30668888 SUPPORT In vitro / ex vivo

"We could not confirm a previous hypothesis on dimerization of mutant TIMP3 proteins."

For this allele the dimerization model was not reproduced, which is why the entry records intramolecular bonding separately.

p.His158Arg Pathogenic

Gene: TIMP3 hgnc:11822 missense variant

A late-onset allele and the first reported coding variant that does not create an unpaired cysteine; the residue is conserved across vertebrate TIMP homologs and modeling places it at a protein-protein interaction interface.

Also known as: H158R

Show evidence (2 references)

PMID:16989765 SUPPORT Human clinical

"A heterozygous His158Arg mutation was found in seven affected family members and was absent from an unaffected member and 98 unrelated controls."

Segregation in seven affected members with absence from controls supports pathogenicity.

PMID:16989765 SUPPORT Human clinical

"Onset of disease occurred in the fifth to seventh decades of life."

Gives the late onset in this family.

TIMP3 signal peptide variants Pathogenic

Gene: TIMP3 hgnc:11822 missense variant

Variants in the N-terminal signal peptide reported in two families with early-onset diffuse maculopathy and no choroidal neovascularization. The reporting authors treat this as a phenotype distinct from classic Sorsby fundus dystrophy, with impaired signal peptide cleavage and defective extracellular deposition rather than accumulation of matrix-bound mutant protein. Recorded here as a variant class with that caveat, not as a subtype, because no separate disease concept exists for it.

Also known as: L10H G12R

Show evidence (2 references)

PMID:35679059 SUPPORT Human clinical

"Eleven individuals from 2 families with early-onset diffuse maculopathy without choroidal neovascularization harbor TIMP3 variants (L10H or G12R) in the N-terminal signaling peptide were analyzed."

Identifies the variants and the families, and records the absence of neovascularization.

PMID:35679059 SUPPORT Human clinical

"This study found that TIMP3 variants altering signal peptide function deviated from classic Sorsby fundus dystrophy both in phenotypic features and underlying mechanism."

The authors' own statement that this group deviates from classic SFD, which is the caveat recorded here.

💊

Medical Actions

7

Intravitreal anti-VEGF therapy for choroidal neovascularization

Action: Pharmacotherapy NCIT:C15986

Agent: bevacizumab NCIT:C2039 ranibizumab NCIT:C67562

Platform: Monoclonal antibody

Intravitreal bevacizumab or ranibizumab is the mainstay for the neovascular complication. A systematic review of 31 cases found good responses when treatment began immediately after symptom onset, with the delay between first symptoms and treatment determining subretinal scar formation and functional prognosis; 11 of 20 eyes with acuity reported before and after treatment kept driving vision, while 5 worsened. A 12-year two-sister series found a treat-and-extend schedule better than pro re nata at preventing recurrence. The therapy addresses the neovascular lesion and not the underlying dystrophy, so atrophic progression continues.

Mechanism Target:

INHIBITS Choroidal Neovascular Membrane Formation — The agents neutralize VEGF in the vitreous and so suppress the neovascular lesion; they do not restore TIMP-3 function or clear the deposit.

Show evidence (1 reference)

PMID:34070857 SUPPORT Human clinical

"In MNV secondary to SFD, the delay between first symptoms and access to anti-VEGF treatment determines subretinal scar formation and thereby, functional prognosis."

The effect on the neovascular lesion and its visual consequence depends on how early the agent is given.

Target Phenotypes: Choroidal neovascularization HP:0011506

Show evidence (4 references)

PMID:34070857 SUPPORT Human clinical

"All papers in common, however, reported satisfied to excellent responses to anti-VEGF therapy if patients were diagnosed and treated immediately after onset of symptoms."

Pooled across 14 publications and one further patient, outcomes were good with prompt treatment.

PMID:34070857 SUPPORT Human clinical

"Of 20 eyes, for which visual acuity was reported before and after treatment, five worsened and seven improved by more than 1 line, whereas eight eyes maintained their function by end of the follow up, and 11 eyes (55%) maintained a driving vision (Snellen VA ≥ 0.5)."

Gives the per-eye outcome distribution, including the eyes that worsened on treatment.

PMID:25766588 SUPPORT Human clinical

"Patients with CNV or PCV showed a favorable response to therapy with intravitreally injected bevacizumab."

Favourable responses to bevacizumab in patients with neovascular and polypoidal lesions.

+ 1 more reference

High-dose oral vitamin A for night blindness

Action: vitamin A supplementation Ontology label: Nutritional Support NCIT:C15433

Agent: vitamin A CHEBI:12777

Platform: Small molecule

Oral vitamin A at 50,000 IU/day abolished night blindness within a week in patients at early stages of disease, and high-dose supplementation markedly improved rod-mediated dark adaptation and dark-adapted thresholds in one patient followed longitudinally. It addresses the local nutritional deficiency produced by the thickened membrane, not the dystrophy, and is off-label; the evidence is a small family study and single-patient longitudinal data.

Mechanism Target:

BYPASSES Photoreceptor Vitamin A Deprivation — Raising systemic vitamin A overcomes the local deficiency created by the transport barrier, without altering the barrier itself.

Show evidence (1 reference)

PMID:7550309 SUPPORT Human clinical

"Nutritional night blindness is thus part of the pathophysiology of this genetic disease and vitamin A supplementation can lead to dramatic restoration of photoreceptor function."

Supplementation restores photoreceptor function, which is the bypass this link records.

Target Phenotypes: Night blindness HP:0000662

Show evidence (3 references)

PMID:7550309 SUPPORT Human clinical

"Vitamin A at 50,000 IU/d was administered orally. Within a week, the night blindness disappeared in patients at early stages of disease."

Gives the dose, the route and the response, and restricts it to early-stage disease.

PMID:34352251 SUPPORT Human clinical

"After high-dose vitamin A supplementation, RMDA and DA thresholds improved markedly."

Longitudinal data from one patient show improved rod-mediated dark adaptation after supplementation.

PMID:34352251 SUPPORT Human clinical

"Improvement of scotopic dysfunction after (off-label) high-dose vitamin A intake, as observed in one patient in our study, is compatible with the hypothesized local deficiency of vitamin A secondary to Bruch's membrane alterations."

Records that the use is off-label and that the observation is from a single patient.

Systemic anti-TNF-alpha therapy (single case report)

Action: Pharmacotherapy NCIT:C15986

Agent: adalimumab NCIT:C65216

Platform: Monoclonal antibody

One 35-year-old patient with aggressive bilateral macular neovascularization and p.Ser204Cys, who showed disease activity on intravitreal bevacizumab and was controlled on repeated intravitreal triamcinolone, had no signs of disease activity over 18 months of subcutaneous adalimumab. The authors propose that the TIMP3 variant raises local tumour necrosis factor alpha because TIMP-3 restrains its shedding by ADAM17. The rationale is untested for this patient's allele. The only measurement a 2024 mechanistic review reports is for a different allele, Ser179Cys (Ser156Cys in secreted-protein numbering), which inhibits ADAM17 as well as wild-type TIMP-3 does; the same review states that the other SFD mutants, Ser204Cys (Ser181Cys) among them, have not been profiled. Because the case for a TNF arm rests on one patient plus TIMP-3 biology measured outside the eye, the entry records the treatment and its single-patient evidence without a mechanism node or pathophysiology target, and holds the question open in the discussions section.

Target Phenotypes: Choroidal neovascularization HP:0011506

Show evidence (4 references)

PMID:34376817 SUPPORT Human clinical

"Because of the high lifetime risk of complication, she was switched to subcutaneous adalimumab and in follow-up over 18 months had no signs of disease activity."

The observed result in the single reported patient.

PMID:34376817 SUPPORT Human clinical

"It is possible with the mutation in the gene for TIMP-3, abnormally high tissue levels of TNFα are produced in the eye."

States the proposed rationale, in the authors' own conditional terms.

PMID:38601018 REFUTE INDIRECT REVIEW SYNTHESIS Other

"showed that the Ser179Cys variant retained the ability to inhibit ADAM17, ADAMTS-4, and ADAMTS-5 to the same degree as wild-type TIMP-3."

Bears against the proposed rationale only by inference: the measured allele is Ser179Cys (Ser156Cys), not the patient's Ser204Cys (Ser181Cys). It shows that at least one SFD allele keeps ADAM17 inhibition, so loss of that inhibition cannot be assumed to be common to the disease.

+ 1 more reference

CRISPR base editing (in silico design only)

Action: Gene Therapy NCIT:C15238

Platform: Gene editing

A bioinformatic analysis in one patient with p.Ser204Cys identified a glycosylase base editor edit that would revert the variant to wild-type at the amino acid level, and an adenine base editor alternative predicted to introduce a tolerated substitution but also a bystander edit. No editing was performed in cells, tissue or animals in that report, so this is a design study rather than a preclinical result.

Show evidence (2 references)

PMID:36421778 SUPPORT Computational

"Using a glycosylase base editor (GBE), another DNA-edit could be introduced that would revert the variant back to wild-type on amino acid level."

Describes the designed correction, which is a computational prediction.

PMID:36421778 SUPPORT Computational

"In silico analyses predicted this variant to be non-pathogenic; however, a bystander edit, p.Ile205Thr, would be introduced."

Records the predicted bystander edit, the limitation of the alternative design.

Laser photocoagulation and photodynamic therapy

Action: laser therapy Ontology label: Laser Therapy NCIT:C15466

Platform: Device

Argon laser photocoagulation and photodynamic therapy were used for neovascular lesions before anti-VEGF agents. In the 42-patient Ser181Cys cohort neither was effective, and individual cases progressed to a disciform scar despite photodynamic treatment. Recorded here because it appears throughout the older literature and because the negative result is what makes anti-VEGF therapy the first choice.

Target Phenotypes: Choroidal neovascularization HP:0011506

Show evidence (2 references)

PMID:18501328 REFUTE Human clinical

"Argon laser therapy and PDT are not effective in treating CNV of patients with this dystrophy."

A 42-patient cohort found neither modality effective, which refutes their use for this indication.

PMID:18501328 SUPPORT Human clinical

"Antiangiogenic agents may be useful in preventing visual loss as a result of this condition."

The same cohort points to antiangiogenic therapy instead, which is the treatment recorded above.

Tobacco avoidance and pulmonary surveillance

Action: smoking cessation intervention Ontology label: Smoking Cessation Intervention NCIT:C15372

Platform: Behavioral / lifestyle

Because TIMP3 variants have been linked to emphysema and bronchiectasis in some families, the report of the eye and lung families and ClinGen's evidence summary both advise affected people to avoid tobacco and to have regular pulmonary examination. This is advice on a non-ocular feature of uncertain penetrance, not a treatment for the retinal disease.

Show evidence (2 references)

PMID:27601084 SUPPORT Human clinical

"In addition, SFD patients should be advised to avoid tobacco consumption, to practice sports, and to undergo regular pulmonary examinations."

The authors' recommendation following the eye and lung families.

CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z SUPPORT Other

"Collectively, these findings suggest that affected patients should be advised to avoid tobacco products and undergo regular pulmonary exams."

ClinGen's evidence summary carries the same advice.

Genetic counseling and carrier surveillance

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counseling for autosomal dominant inheritance with reported complete penetrance and variable age of onset, and cascade testing of relatives. Because structural and scotopic abnormalities precede symptoms, identified carriers can be monitored for the neovascular complication, which responds best when treated immediately.

Show evidence (2 references)

PMID:25766588 SUPPORT Human clinical

"Imaging using late-phase ICG-A may be useful for early identification of individuals at risk for developing SFD."

Identification of at-risk relatives is the purpose that cascade testing and surveillance serve here.

PMID:34070857 SUPPORT Human clinical

"If treated early, this is generally favourable under regular controls and a consequent anti-VEGF treatment of MNV activity."

Supports monitoring identified carriers so that treatment can start promptly.

🔬

Diagnosis

2

Multimodal retinal imaging

Optical coherence tomography shows irregular thickening of Bruch's membrane and the sub-RPE deposit; optical coherence tomography angiography shows choriocapillaris flow deficits and detects neovascular membranes; late-phase indocyanine green angiography shows reduced fluorescence, which has been proposed for identifying carriers at risk before symptoms; fundus autofluorescence is frequently abnormal, and reticular pseudodrusen appear on it as hypoautofluorescent lesions. Early neovascularization in a patient with no predisposing factor such as high myopia should prompt the diagnosis.

eye examination NCIT:C38060

Show evidence (4 references)

PMID:27601084 SUPPORT Human clinical

"Despite variable and confounding phenotypes, this dystrophy should be considered in patients with early neovascularization in absence of predisposing factors such as high myopia, or with irregular thickening of the Bruch membrane as shown on SD-OCT."

States the two findings that should raise the diagnosis, and names the imaging modality.

PMID:25766588 SUPPORT Human clinical

"Imaging using late-phase ICG-A may be useful for early identification of individuals at risk for developing SFD."

Proposes late-phase indocyanine green angiography for early identification.

ORPHA:59181 SUPPORT Other

"HP:0030602 | Abnormal fundus autofluorescence imaging | Frequent (79-30%)"

Orphanet records abnormal fundus autofluorescence as frequent, which is the basis for listing the modality here.

+ 1 more reference

TIMP3 molecular genetic testing

Diagnosis is confirmed by finding a heterozygous TIMP3 variant. Testing is directed at exon 5 first, since most alleles lie there, but exon 1 and the signal peptide sequence carry reported variants too, so a negative exon 5 result does not exclude the disease.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:23099917 SUPPORT Human clinical

"DNA analysis revealed the presence of mutation c.610A>T (p.Ser204Cys) in exon 5 of the TIMP3 gene and confirmed the diagnosis of Sorsby fundus dystrophy."

Molecular testing confirmed the clinical diagnosis in a case.

PMID:30668888 SUPPORT Human clinical

"Haplotype reconstruction in three SFD families revealed that the identified c.113C>G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late-onset SFD phenotype."

An exon 1 founder allele, which is why testing cannot be confined to exon 5.

📈

Progression

4

Preclinical carrier stage

Variant carriers without symptoms already show thickening of Bruch's membrane and choriocapillaris thinning on optical coherence tomography angiography, and reduced late-phase indocyanine green fluorescence; rod dark adaptation can be slowed before any change is visible on multimodal imaging.

Show evidence (2 references)

PMID:35483032 SUPPORT Human clinical

"Swept-source optical coherence tomography angiography imaging can detect BM and CC abnormalities in vivo in subjects unaware of their TIMP3 status in a family with SMD."

Structural change is detectable before clinical disease in carriers.

PMID:34352251 SUPPORT Human clinical

"whereas RMDA could be slowed even in the absence of fundus alterations on multimodal imaging"

Rod-mediated dark adaptation is abnormal before imaging shows fundus change.

Early symptomatic stage

Night blindness, dark adaptation difficulty and visual field defects appear first in some families, while in others metamorphopsia or reduced acuity is the presenting complaint. Best-corrected acuity can still be normal while scotopic function is already impaired.

Show evidence (1 reference)

PMID:34352251 SUPPORT Human clinical

"In contrast to BCVA, scotopic visual function tests are suitable to quantify dysfunction in the early stages."

Records that rod-driven function, not best-corrected acuity, is what is abnormal early.

Neovascular stage

Sudden central vision loss from a choroidal neovascular membrane, at a median of 46 years in the first eye and 50 years in the second in the Ser181Cys cohort, with vision falling to 20/200 or below about two years later if untreated.

Show evidence (1 reference)

PMID:18501328 SUPPORT Human clinical

"The median age at onset of CNV in the first eye was 46.1 years and in the second eye was 50.3 years."

Gives the median ages of neovascular onset in each eye.

Atrophic end stage

Widespread chorioretinal atrophy, fibrosis and choroidal thinning, uniform across families in late disease, with loss first of central and then of peripheral vision.

Show evidence (2 references)

PMID:25766588 SUPPORT Human clinical

"Late disease manifestations were uniform with widespread chorioretinal atrophy, fibrosis, and choroidal thinning."

Describes the end-stage picture.

ORPHA:59181 SUPPORT Other

"leading to loss of central vision, then peripheral vision, and eventually blindness"

Orphanet's definition gives the order in which vision is lost.

📊

Prevalence

1

Worldwide

Point prevalence 0.45 per 100,000 1–9 per 1,000,000

From the estimate of 1 in 220,000 given in a review of the disease, which is 0.45 per 100,000. Orphanet records its own point-prevalence class as unknown.

Show evidence (2 references)

PMID:28847738 SUPPORT REVIEW SYNTHESIS Other

"Sorsby fundus dystrophy (SFD) is an autosomal dominant macular dystrophy with an estimated prevalence of 1 in 220,000 and an onset of disease around the 4th to 6th decade of life."

Gives the prevalence estimate this record normalizes.

ORPHA:59181 SUPPORT Other

"Unknown | Worldwide | Point prevalence | ORPHANET"

Orphanet records the worldwide point-prevalence class as unknown.

🧫

Experimental Models

1

Patient-derived SFD iPSC-RPE IPSC_DERIVED_MODEL

Patient iPSC-RPE accumulates TIMP3 in its extracellular matrix, forms sub-RPE deposits resembling those in affected donor globes, shows extracellular matrix and angiogenesis-related protein changes, and is more vulnerable to oxidative stress. Correcting the variant reduces the deposits. The two main studies disagree on the dimerization question: one found TIMP3 dimers in both patient and control cultures and no change in VEGF secretion, which is the main published challenge to dimerization as the driving lesion.

Organism

human NCBITaxon:9606

Cell source

Retinal pigment epithelium differentiated from induced pluripotent stem cells of patients carrying TIMP3 p.Ser204Cys, compared with unaffected controls, with isogenic CRISPR-corrected clones in one study

Publication

PMID:32666594

Pathograph links

TIMP-3 Accumulation in Bruch's Membrane partially recapitulates fidelity: moderate observes: cellular Reproduces the accumulation of TIMP3 in the matrix beneath the RPE and the sub-RPE deposit.

Limitations: Cultured RPE has no choroid, no full five-layered Bruch's membrane and no photoreceptors, so the deposit is deposit-like rather than the clinical lesion.

Show evidence (2 references)

PMID:34929159 SUPPORT In vitro / ex vivo

"We found that SFD iPSC-RPE formed significantly more sub-RPE deposits (∼6-90 μm in height) compared to control RPE at 8 weeks."

Quantifies the deposits formed by patient-derived RPE against controls.

+ 1 more reference

Resistance of Mutant TIMP-3 to Extracellular Matrix Turnover partially recapitulates fidelity: moderate observes: cellular Patient RPE accumulates TIMP3 basolaterally with no change in gene expression, which is the post-translational accumulation this node describes. The same study did not find mutant-specific dimerization.

Limitations: Turnover itself was not measured in this system; the accumulation is inferred from protein level against unchanged transcript level.

Show evidence (2 references)

PMID:32666594 SUPPORT In vitro / ex vivo

"SFD-hiPSC-RPE exhibited basolateral accumulation of TIMP3 monomers, despite no change in TIMP3 gene expression."

Accumulation without transcriptional change in patient-derived RPE.

+ 1 more reference

Show evidence (2 references)

PMID:32666594 SUPPORT In vitro / ex vivo

"Our findings provide a proof-of-concept that SFD patient-derived hiPSC-RPE mimic mature RPE cells and support the hypothesis that excess accumulation of mutant TIMP3, rather than an absence or deficiency of functional TIMP3, drives ECM and angiogenesis-related changes in SFD."

States what the model supports, which is the accumulation mechanism this entry curates.

PMID:28878022 SUPPORT In vitro / ex vivo

"Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid- and protein-rich "drusen-like" composition."

Patient RPE from three dominant macular dystrophies, Sorsby among them, forms drusen-like deposits.

🐁

Animal Models

1

Timp3 S156C knock-in mouse

A knock-in carrying the disease-associated Ser156Cys substitution in the orthologous murine gene. At 8 months it shows abnormalities of the inner aspect of Bruch's membrane and of the adjacent RPE basal microvilli, with increased Timp3 in Bruch's membrane, while retinal function recorded electrodiagnostically stays normal for life. Comparable changes appear in normal littermates only at 30 months. The same allele shows reduced MMP inhibition with raised MMP2 and bFGF and accentuated laser induced choroidal neovascular leakage, more membrane-associated VEGFR-2 in endothelium, and RPE and photoreceptor degeneration at sodium iodate doses that spare wild-type mice.

Species

Mouse

Genotype

Timp3 Ser156Cys knock-in (written S179C where the signal peptide is counted)

Publication

PMID:12147610

Pathograph links

TIMP-3 Accumulation in Bruch's Membrane recapitulates fidelity: moderate observes: tissue Reproduces the accumulation of Timp3 in Bruch's membrane and the membrane abnormality.

Limitations: Mice have no macula, the change is ultrastructural rather than a clinical drusen phenotype, and it is an acceleration of a change that wild-type mice reach at 30 months.

Show evidence (2 references)

PMID:12147610 SUPPORT Model organism

"The localization of the mutant protein in the eye is normal, although there is evidence of increased Timp3 levels in Bruch's membrane of mutant animals."

The knock-in shows increased Timp3 in the membrane with normal localization.

+ 1 more reference

Choroidal Neovascular Membrane Formation partially recapitulates fidelity: moderate observes: tissue Neovascular leakage is accentuated in mutant mice, but only after laser injury rather than spontaneously.

Limitations: The neovascular lesion requires laser injury to provoke it, so the model reports susceptibility rather than the spontaneous membranes patients develop.

Show evidence (1 reference)

PMID:31757977 SUPPORT Model organism

"In this study we demonstrate that mice expressing mutant TIMP3 (Timp3S179C/S179C) showed reduced MMP inhibitory activity with an increase in MMP2 activity and bFGF levels, as well as accentuated CNV leakage when subjected to laser injury."

Records the accentuated neovascular leakage and that laser injury was needed.

Increased RPE Susceptibility to Oxidative Stress recapitulates fidelity: moderate observes: cellular Mutant RPE carries a baseline antioxidant response and degenerates at oxidative doses that spare wild-type tissue.

Readouts

RPE and photoreceptor degeneration after low-dose sodium iodate

Direction: INCREASED

Interpretation: A controlled oxidative challenge separates mutant from wild-type tissue.

Show evidence (1 reference)

PMID:32828705 SUPPORT Model organism

"The RPE and photoreceptors in Timp3 mutant mice degenerated at low doses of sodium iodate, which had no effect in wildtype control mice."

Gives the measured difference between mutant and wild-type mice.

Show evidence (1 reference)

PMID:32828705 SUPPORT Model organism

"These studies suggest that TIMP3 mutations may result in a dysregulation of pro-oxidant-antioxidant homeostasis in the RPE, leading to RPE degeneration in SFD."

The authors' reading of the model as informative for the oxidative mechanism.

Impaired TIMP-3 Inhibition of VEGFR2 recapitulates fidelity: moderate observes: molecular Mutant mouse endothelium carries more membrane-associated VEGFR-2, the same change reported in human SFD eyes.

Show evidence (1 reference)

PMID:19478078 SUPPORT Model organism

"Timp-3S156C/S156C mice have reduced TIMP-3 activity and increased expression of VEGFR-2."

The mouse result on its own: reduced inhibitory activity with raised VEGFR-2 expression. The paper's summary sentence covering both mouse and human eyes is cited on the pathophysiology node instead, so that each item here carries one kind of evidence.

Show evidence (2 references)

PMID:12147610 SUPPORT Model organism

"The knock-in mice display early features of age-related changes in Bruch's membrane and the RPE that may represent the primary clinical manifestations of SFD."

The authors' own statement of what the model represents.

PMID:12147610 SUPPORT Model organism

"Long-term electrodiagnostic recordings indicated normal retinal function throughout life."

Records the limitation that retinal function stays normal in the model.

{ }

Source YAML

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name: Sorsby Fundus Dystrophy
creation_date: "2026-10-31T14:00:00Z"
category: Mendelian
description: >-
  Sorsby fundus dystrophy (SFD) is a rare autosomal dominant macular dystrophy
  caused by heterozygous variants in TIMP3, which encodes tissue inhibitor of
  metalloproteinases-3, an extracellular-matrix-bound inhibitor of matrix
  metalloproteinases that also blocks VEGF binding to VEGF receptor-2. Most
  disease-causing variants lie in exon 5, which encodes almost all of the
  C-terminal domain, and most add or remove a cysteine residue; the mutant
  protein forms aberrant disulfide-bonded dimers and multimers, resists turnover
  from the extracellular matrix and accumulates in Bruch's membrane. TIMP-3 is
  made by the retinal pigment epithelium (RPE) and normally resides in Bruch's
  membrane, so the accumulation thickens that membrane and produces confluent
  sub-RPE deposits and drusen-like lesions across the fundus. Two consequences
  follow. The thickened membrane impairs exchange between the choroid and the
  photoreceptors, giving night blindness and delayed dark adaptation that
  high-dose vitamin A can reverse at early stages; and the dimerized protein no
  longer restrains VEGFR2, while reduced metalloproteinase inhibition raises
  MMP2 activity and basic fibroblast growth factor release, so choroidal
  neovascularization develops and is the main cause of blindness. Symptoms begin
  in the third to sixth decade, typically the fourth to fifth, with sudden
  central vision loss from neovascularization or macular atrophy, progressing to
  widespread chorioretinal atrophy. Penetrance is reported as complete.
  Intravitreal anti-VEGF therapy preserves central vision when started promptly;
  argon laser and photodynamic therapy are not effective. Because SFD reproduces
  the drusen, neovascular and atrophic biology of age-related macular
  degeneration from a single genetic lesion, it is used as a monogenic model of
  that disease.
disease_term:
  preferred_term: Sorsby fundus dystrophy
  term:
    id: MONDO:0007640
    label: Sorsby fundus dystrophy
synonyms:
- SFD
- Sorsby macular dystrophy
- SMD
- Sorsby pseudoinflammatory fundus dystrophy
- Sorsby pseudoinflammatory macular dystrophy
- hemorrhagic macular dystrophy
parents:
- Ophthalmological Disease
- Macular Dystrophy
- Inherited retinal dystrophy
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: NEUROLOGIC
notes: >-
  Naming. "Sorsby Fundus Dystrophy" is kept rather than a gene-related dyad: no
  MONDO label or exact synonym, OMIM title, ClinGen-preferred label or
  GeneReviews chapter title uses a TIMP3-related form for this disease, and the
  eponym is specific to the single-gene entity ClinGen curates. The MONDO label,
  the Orphanet synonyms and the historical pseudoinflammatory names are kept in
  synonyms. Note that "TIMP3-related retinopathy" does appear in the literature
  (PMID:35679059) for a phenotype the authors distinguish from classic SFD, so
  adopting it as this entry's name would widen the scope.
  Scope, and why the MONDO descendant is left out. MONDO:0009918 "fundus
  dystrophy, pseudoinflammatory, recessive form" (OMIM 264420) is a descendant
  of this entry's term and is not curated as a has_subtypes entry. That concept
  rests on one consanguineous Finnish family reported as autosomal recessive
  (PMID:7148944). The same family was later found to carry a heterozygous
  Gly166Cys TIMP3 variant segregating with disease, which the authors read as
  autosomal dominant inheritance, and ClinGen's lumping and splitting assessment
  records the proposed recessive mechanism as refuted. MONDO records no causal
  gene for MONDO:0009918 (read from the OLS MONDO record for that term), so
  there is no sourced TIMP3 basis on which to curate it as a distinct subtype;
  both statements are cited in the inheritance block. The entity is left out
  rather than mapped, and the lump follows ClinGen's own decision to treat
  TIMP3-variant cases as one disease.
  Deliberately lumped. Early-onset and late-onset presentations, and the
  N-terminal (exon 1) and C-terminal (exon 5) variant classes, are kept in one
  entry rather than split into subtypes. ClinGen's Retina GCEP found the
  molecular mechanism and the autosomal dominant inheritance pattern consistent
  across unrelated patients and judged the phenotypic variability, early versus
  late onset in particular, to be a spectrum rather than separate entities.
  Signal-peptide variants (L10H, G12R) are the one reported group whose authors
  argue for a distinct entity; they are recorded in the genetic section with
  that caveat rather than as a subtype, because the cited series reports no
  choroidal neovascularization and a different biochemical defect, and no
  separate disease concept for them exists in MONDO.
  No GeneReviews chapter names this disease or TIMP3: PubMed searches
  '"Sorsby"[TI] AND genereviews[book] NOT retired[TI]', 'Sorsby[TIAB] AND
  genereviews[book] NOT retired[TI]' and 'TIMP3[TIAB] AND genereviews[book] NOT
  retired[TI]' each returned zero, and the committed Bookshelf index holds no
  matching chapter. The phenotype baseline here is therefore the Orphanet HPO
  annotation set (ORPHA:59181), the ClinGen evidence summary and the primary
  clinical series.
  Variant numbering in this literature is inconsistent: positions are quoted
  both with and without the 23-residue signal peptide, so the same allele
  appears as S156C or S179C, S181C or S204C, and Y168C or Y191C. The
  conventional numbering of the secreted protein is used in the variant names
  here, with the alternative given in the variant synonyms where a cited source
  uses it.
  Diagnostic imaging modalities are described in the diagnosis entries rather
  than bound in their `measurements` slots, whose range is restricted to LOINC
  codes; the NCIT procedure terms for optical coherence tomography and
  indocyanine green angiography cannot sit there.
pathophysiology:
- name: TIMP3 Cysteine-Altering Variant
  description: >-
    A heterozygous TIMP3 variant, in most reported cases a missense change in
    exon 5 affecting the C-terminal domain of the protein, adds or removes a
    cysteine residue and so disturbs the arrangement of the conserved cysteines
    and disulfide bonds that hold the tertiary structure together. A minority of
    reported alleles do not alter a cysteine (for example His158Arg) or lie
    outside exon 5 (Ser38Cys in exon 1), and one nonsense allele leaves an
    unpaired cysteine. Mutant protein continues to be expressed and to localize
    to the extracellular matrix, so the primary consequence is an altered
    protein rather than its absence.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TIMP3
    term:
      id: hgnc:11822
      label: TIMP3
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    allele_type: missense
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  molecular_functions:
  - preferred_term: TIMP-3 metalloendopeptidase inhibitor activity
    term:
      id: GO:0008191
      label: metalloendopeptidase inhibitor activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:7894485
    reference_title: Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have now identified point mutations in the TIMP3 gene in affected members of two SFD pedigrees."
    explanation: The gene discovery study identified TIMP3 point mutations in affected members of two SFD families.
  - reference: PMID:7894485
    reference_title: Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These mutations are predicted to disrupt the tertiary structure and thus the functional properties of the mature protein."
    explanation: States the predicted structural consequence of the variants on the mature protein.
  - reference: PMID:28847738
    reference_title: Sorsby fundus dystrophy - A review of pathology and disease mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Most SFD-associated TIMP3 variants involve the gain or loss of a cysteine residue."
    explanation: A review of the reported variant set states that most alter a cysteine residue.
  - reference: PMID:37013036
    reference_title: Evidence that all Sorsby's fundus dystrophy mutations cause TIMP3 dimerization resulting in impaired inhibition of VEGFR2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Notably, eleven mutations result in a change to a cysteine residue, while the nonsense mutation (E139X), also gives rise to an unpaired cysteine residue."
    explanation: Counts the cysteine-altering alleles among the fifteen TIMP3 variants known at the time.
  - reference: PMID:16989765
    reference_title: A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His158Arg is the first reported TIMP3 SFD coding sequence mutation that does not create an unpaired cysteine."
    explanation: Documents the exception, a disease-causing allele that does not alter a cysteine.
  downstream:
  - target: Aberrant TIMP-3 Disulfide Bonding and Multimerization
    causal_link_type: DIRECT
    description: >-
      The unpaired cysteine introduced by the variant forms intermolecular or
      aberrant intramolecular disulfide bonds, so the mutant protein dimerizes
      or multimerizes.
    evidence:
    - reference: PMID:10854443
      reference_title: A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in Sorsby's fundus dystrophy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "However, unlike wild-type TIMP-3, they all form dimers."
      explanation: Expressing the mutant alleles shows that dimer formation, absent for wild-type protein, is common to them.
    - reference: PMID:30668888
      reference_title: The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our data provide evidence for disruption of the established Cys36-Cys143 disulfide bond and formation of a novel Cys36-Cys38 bond, possibly associated with increased glycosylation of the protein."
      explanation: For the N-terminal allele the aberrant bonding is intramolecular rather than a dimer, which is why this node is written as aberrant disulfide bonding generally.
  - target: Increased MMP2 Activity and bFGF Release
    causal_link_type: DIRECT
    description: >-
      Mutant TIMP-3 restrains metalloproteinases less well in vivo, raising MMP2
      activity and the level of basic fibroblast growth factor.
    evidence:
    - reference: PMID:31757977
      reference_title: Sorsby Fundus Dystrophy Mutation in Tissue Inhibitor of Metalloproteinase 3 (TIMP3) promotes Choroidal Neovascularization via a Fibroblast Growth Factor-dependent Mechanism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In this study we demonstrate that mice expressing mutant TIMP3 (Timp3S179C/S179C) showed reduced MMP inhibitory activity with an increase in MMP2 activity and bFGF levels, as well as accentuated CNV leakage when subjected to laser injury."
      explanation: In the knock-in mouse the mutant protein is associated with reduced MMP inhibition, higher MMP2 activity and raised bFGF.
  - target: RPE Glucose and Glutamine Metabolic Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Mutant TIMP3 is accompanied by a metabolism-weighted change in the RPE
      proteome and by raised glycolytic flux; how the extracellular protein
      produces the intracellular metabolic change is not established.
    evidence:
    - reference: PMID:39047907
      reference_title: Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Quantitative proteomics and enrichment analysis conducted on RPE of mice expressing mutant S179C TIMP3 identified differentially expressed proteins that were enriched for metabolism-related pathways and processes."
      explanation: In mutant mouse RPE the differentially expressed proteins are enriched for metabolic pathways, which is what links the variant to this node.
  - target: Increased RPE Susceptibility to Oxidative Stress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Mutant Timp3 is associated with a pro-oxidant state in the RPE; the steps
      between the altered protein and that state are not established.
    evidence:
    - reference: PMID:32828705
      reference_title: The retinal pigment epithelium in Sorsby Fundus Dystrophy shows increased sensitivity to oxidative stress-induced degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Antioxidant genes are increased at baseline in the RPE in SFD mouse models, but not in the retina."
      explanation: The mutant mouse RPE shows a baseline antioxidant gene response, which the authors read as a pro-oxidant environment.
- name: Aberrant TIMP-3 Disulfide Bonding and Multimerization
  description: >-
    Mutant TIMP-3 forms disulfide-bonded dimers and higher-molecular-weight
    complexes in the extracellular matrix. The complexes retain the protein's
    metalloproteinase-inhibitory activity and its matrix localization in most
    assays, so the molecular lesion is an altered quaternary state rather than a
    dead enzyme inhibitor. Two separable consequences follow: the complexes
    resist turnover, and they inhibit VEGFR2 less well.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: aberrant TIMP-3 protein dimerization
    term:
      id: GO:0046983
      label: protein dimerization activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: TIMP-3 multimer formation
    term:
      id: GO:0051260
      label: protein homooligomerization
    modifier: INCREASED
  evidence:
  - reference: PMID:37013036
    reference_title: Evidence that all Sorsby's fundus dystrophy mutations cause TIMP3 dimerization resulting in impaired inhibition of VEGFR2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In summary, our data support the hypothesis that all SFD-mutated forms of TIMP3 result in dimerization/multimerization of the protein which in turn significantly impairs its ability to inhibit the proangiogenic growth factor receptor VEGFR2."
    explanation: Expression of the full reported variant set in RPE-derived cells supports dimerization or multimerization as a common molecular phenotype.
  - reference: PMID:9642234
    reference_title: Localization of the functional domains of human tissue inhibitor of metalloproteinases-3 and the effects of a Sorsby's fundus dystrophy mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This gave rise to an additional 48-kDa species (possibly a TIMP-3 dimer) that retained its ability to inhibit MMPs and localize to the ECM."
    explanation: The Ser181Cys protein forms an extra species of about twice the monomer mass while keeping inhibitory activity and matrix binding.
  - reference: PMID:11827795
    reference_title: "Sorsby's fundus dystrophy tissue inhibitor of metalloproteinases-3 (TIMP-3) mutants have unimpaired matrix metalloproteinase inhibitory activities, but affect cell adhesion to the extracellular matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Two of the mutants (Ser156Cys and Ser181Cys) showed a marked propensity to form multiple higher molecular-weight complexes that retained TIMP activity on reverse zymography."
    explanation: Documents higher-molecular-weight complexes that keep inhibitory activity, for two of the four mutants assayed.
  - reference: PMID:11827795
    reference_title: "Sorsby's fundus dystrophy tissue inhibitor of metalloproteinases-3 (TIMP-3) mutants have unimpaired matrix metalloproteinase inhibitory activities, but affect cell adhesion to the extracellular matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings indicate that the pathogenesis of Sorsby's fundus dystrophy cannot be attributed to a failure to localize SFD TIMP-3 proteins to the ECM or defects in MMP inhibition, but may involve the formation of aberrant TIMP-3-containing protein complexes and altered cell adhesion."
    explanation: Supports writing the node as an altered quaternary state rather than as loss of matrix binding or of inhibitory function.
  - reference: PMID:36430707
    reference_title: "Deglycosylation Increases the Aggregation and Angiogenic Properties of Mutant Tissue Inhibitor of Metalloproteinase 3 Protein: Implications for Sorsby Fundus Dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results suggest that even though mutant TIMP3 proteins are more glycosylated, post-translational deglycosylation may play a critical role in the aggregation of mutant TIMP3 and contribute to the pathogenesis of SFD."
    explanation: >-
      Adds a modifier of the aggregation step: mutant protein is more
      glycosylated, and removing that glycosylation drives it to aggregate.
  downstream:
  - target: Resistance of Mutant TIMP-3 to Extracellular Matrix Turnover
    causal_link_type: DIRECT
    description: >-
      Intermolecular disulfide bonding is what makes the mutant proteins
      resistant to turnover from the matrix.
    evidence:
    - reference: PMID:16223891
      reference_title: Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This showed that resistance to turnover, resulting from intermolecular disulfide bond formation, was a common property of all the SFD mutants examined, providing a possible explanation for the increased deposition of the protein observed in eyes from SFD patients."
      explanation: Attributes the turnover resistance of every mutant examined to intermolecular disulfide bonding.
  - target: Impaired TIMP-3 Inhibition of VEGFR2
    causal_link_type: DIRECT
    description: >-
      Dimerization about the C-terminal domain, the part of the molecule that is
      necessary and sufficient for receptor inhibition, impairs inhibition of
      VEGFR2.
    evidence:
    - reference: PMID:37013036
      reference_title: Evidence that all Sorsby's fundus dystrophy mutations cause TIMP3 dimerization resulting in impaired inhibition of VEGFR2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This led us to hypothesize that dimerization of TIMP3 about the carboxyl domain may impair the ability of all mutant TIMP3 proteins to inhibit VEGFR2, potentially explaining the CNV which is a hallmark of this disease."
      explanation: States the proposed link from dimerization to loss of VEGFR2 inhibition, which the study then tested.
- name: Resistance of Mutant TIMP-3 to Extracellular Matrix Turnover
  description: >-
    Disulfide-linked mutant TIMP-3 is cleared from the extracellular matrix more
    slowly than wild-type protein by retinal pigment epithelial cells. Transcript
    levels are not raised in affected eyes, so the accumulation is
    post-translational rather than an increase in expression. The process is
    bound as protein catabolism of TIMP-3, decreased, because the defect is the
    clearance of one protein from the matrix, not breakdown of the matrix as a
    whole.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: TIMP-3 turnover from the extracellular matrix
    term:
      id: GO:0030163
      label: protein catabolic process
    modifier: DECREASED
  cellular_components:
  - preferred_term: extracellular matrix
    term:
      id: GO:0031012
      label: extracellular matrix
  evidence:
  - reference: PMID:16223891
    reference_title: Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data show that increased deposition of active TIMP-3, rather than dysregulation of metalloproteinase inhibition, is likely to be the primary, initiating event in SFD."
    explanation: The authors' conclusion from expressing the mutants in human RPE cells, that deposition of still-active protein is the initiating event.
  - reference: PMID:14597066
    reference_title: TIMP-3 mRNA is not overexpressed in Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a reduction of mRNA expression of MMP-2 and TIMP-3 in the Sorsby retinal pigment epithelium cells."
    explanation: In situ hybridization in an SFD donor eye shows no transcriptional overexpression, so accumulation is not driven by increased synthesis.
  - reference: PMID:9642234
    reference_title: Localization of the functional domains of human tissue inhibitor of metalloproteinases-3 and the effects of a Sorsby's fundus dystrophy mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data favor the hypothesis that the TIMP-3 mutations seen in Sorsby's fundus dystrophy contribute to disease progression by accumulation of mutant protein rather than by the loss of functional TIMP-3."
    explanation: Supports accumulation rather than loss of function as the route from the variant to disease.
  downstream:
  - target: TIMP-3 Accumulation in Bruch's Membrane
    causal_link_type: DIRECT
    description: >-
      Because TIMP-3 is secreted by the RPE into Bruch's membrane, protein that
      is not turned over accumulates there.
    evidence:
    - reference: PMID:9924344
      reference_title: Accumulation of tissue inhibitor of metalloproteinases-3 in human eyes with Sorsby's fundus dystrophy or retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "TIMP-3 is a component of the increased ECM sequestered in Bruch's membrane in SFD."
      explanation: Immunolocalization in SFD donor eyes places the accumulated protein in Bruch's membrane.
- name: TIMP-3 Accumulation in Bruch's Membrane
  description: >-
    TIMP-3 is made by the retinal pigment epithelium and is normally a component
    of Bruch's membrane, where it regulates the thickness of that matrix by
    inhibiting matrix metalloproteinases. In SFD eyes the thickened membrane and
    the sub-RPE deposits label strongly for TIMP-3, and the protein is increased
    in the extracellular matrix of patient-derived RPE, so the mutant protein
    accumulates in the compartment where the wild-type protein normally works.
  biological_scale: TISSUE
  locations:
  - preferred_term: Bruch's membrane
    term:
      id: UBERON:0003957
      label: Bruch's membrane
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  cellular_components:
  - preferred_term: basement membrane
    term:
      id: GO:0005604
      label: basement membrane
  evidence:
  - reference: PMID:9006347
    reference_title: Tissue inhibitor of metalloproteinases-3 is a component of Bruch's membrane of the eye.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results indicate that TIMP-3 is an extracellular matrix component of Bruch's membrane."
    explanation: Establishes the normal location of the protein, which is the compartment this node is about.
  - reference: PMID:8759363
    reference_title: Localization of TIMP-3 mRNA expression to the retinal pigment epithelium.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TIMP-3 mRNA expression was detected strongly in the retinal pigment epithelium (RPE) and to a minor extent in the ciliary epithelium, but not at any other site within the eye."
    explanation: In situ hybridization in mouse eyes identifies the RPE as the ocular source of the protein.
  - reference: PMID:9924344
    reference_title: Accumulation of tissue inhibitor of metalloproteinases-3 in human eyes with Sorsby's fundus dystrophy or retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the SFD eyes, the thickened Bruch's membrane was strongly TIMP-3 positive except where RPE cells had degenerated."
    explanation: Donor eyes with a confirmed TIMP3 variant show TIMP-3 accumulation in the thickened membrane.
  - reference: PMID:10711711
    reference_title: TIMP-3, collagen, and elastin immunohistochemistry and histopathology of Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In SFD, immunolabeling of TIMP-3 also was present in the sub-RPE deposit and in the inner portion of the ciliary body deposit."
    explanation: Places the accumulated protein in the sub-RPE deposit as well as in Bruch's membrane.
  - reference: PMID:34929159
    reference_title: Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We detected a ∼18-fold increase in TIMP3 accumulation in the extracellular matrix (ECM) of SFD RPE"
    explanation: Quantifies the accumulation in the matrix of patient-derived RPE.
  - reference: PMID:28847738
    reference_title: Sorsby fundus dystrophy - A review of pathology and disease mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "An important function of TIMP3 within the outer retina is to regulate the thickness of Bruch's membrane."
    explanation: States the normal function in this compartment whose disturbance the next node describes.
  downstream:
  - target: Bruch's Membrane Thickening and Sub-RPE Deposit Formation
    causal_link_type: DIRECT
    description: >-
      Sequestration of excess TIMP-3 and matrix in Bruch's membrane thickens it
      and builds confluent deposits beneath the RPE basement membrane.
    evidence:
    - reference: PMID:9924344
      reference_title: Accumulation of tissue inhibitor of metalloproteinases-3 in human eyes with Sorsby's fundus dystrophy or retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Mutations in the TIMP3 gene cause Sorsby's fundus dystrophy (SFD), which is characterised by thickening of Bruch's membrane, choroidal neovascularisation, and photoreceptor degeneration."
      explanation: Ties the TIMP3 lesion to membrane thickening in affected eyes.
- name: Bruch's Membrane Thickening and Sub-RPE Deposit Formation
  description: >-
    Confluent amorphous deposits, about 20 to 30 micrometres thick, lie between
    the RPE basement membrane and the inner collagenous layer of Bruch's
    membrane, and the membrane itself is thickened; the deposits contain
    collagens, elastin, glycosaminoglycans, lipids and calcium, and the elastic
    layer of Bruch's membrane is morphologically altered. Unlike age-related
    macular degeneration the thickening is diffuse rather than confined to the
    macula, and it is detectable by optical coherence tomography in carriers who
    have no symptoms. The deposits are the structural lesion that underlies the
    drusen-like fundus lesions, the transport barrier and the choriocapillaris
    changes.
  biological_scale: TISSUE
  locations:
  - preferred_term: Bruch's membrane
    term:
      id: UBERON:0003957
      label: Bruch's membrane
  biological_processes:
  - preferred_term: Bruch's membrane extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32828705
    reference_title: The retinal pigment epithelium in Sorsby Fundus Dystrophy shows increased sensitivity to oxidative stress-induced degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The predominant histopathological feature in the eyes of patients with SFD are confluent, 20–30 μm thick, amorphous deposits found between the basement membrane of the retinal pigment epithelium (RPE) and the inner collagenous layer of Bruch's membrane."
    explanation: Gives the location and thickness of the defining deposit.
  - reference: PMID:10711711
    reference_title: TIMP-3, collagen, and elastin immunohistochemistry and histopathology of Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both deposits contained collagens, elastin, glycosaminoglycans, lipids, and calcium."
    explanation: Gives the composition of the sub-RPE deposit in a donor eye with a confirmed variant.
  - reference: PMID:10711711
    reference_title: TIMP-3, collagen, and elastin immunohistochemistry and histopathology of Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy revealed a morphologically altered elastic layer of the Bruch's membrane."
    explanation: Documents the structural change in the membrane itself.
  - reference: PMID:30668888
    reference_title: The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "however the diffuse Bruch membrane thickening observed in SFD is not limited to the macula as in AMD"
    explanation: Records that the thickening is diffuse, the feature that separates it from age-related macular degeneration.
  - reference: PMID:35483032
    reference_title: SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY DETECTION OF BRUCH MEMBRANE AND CHORIOCAPILLARIS ABNORMALITIES IN SORSBY MACULAR DYSTROPHY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His niece, despite having no clinical evidence of SMD, showed BM thickening and CC thinning on SS-OCTA."
    explanation: The membrane change is present in a variant carrier with no clinical disease, so it precedes symptoms.
  downstream:
  - target: Impaired Transport Across Bruch's Membrane
    causal_link_type: DIRECT
    description: >-
      The thickened, deposit-laden membrane is a diffusion barrier between the
      choroidal blood supply and the outer retina.
    evidence:
    - reference: PMID:1559761
      reference_title: Abnormal dark adaptation and rhodopsin kinetics in Sorsby's fundus dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "It was hypothesized that the abnormal dark adaptation and rhodopsin kinetics might be caused by reduced metabolic exchange across a thickened Bruch's membrane."
      explanation: >-
        Psychophysics in eight patients showed that the scotopic defect followed
        the distribution of the deposit; the barrier step itself is the authors'
        inference from that correlation rather than a measurement of transport.
  - target: Choriocapillaris Flow Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Choriocapillaris flow deficits accompany the sub-RPE deposits but extend
      beyond them, so the deposit does not simply mask the vessels and the
      intermediate steps are undefined.
    evidence:
    - reference: PMID:34844251
      reference_title: Choriocapillaris Flow Signal Impairment in Sorsby Fundus Dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with early SFD exhibit pronounced abnormalities of CC flow signal on OCTA, which are not limited to areas of sub-RPE deposits seen on OCT imaging."
      explanation: Flow deficits are present in early disease and are not confined to the deposits, which is why this edge is written as indirect.
  - target: Drusen-like sub-RPE deposits
    causal_link_type: DIRECT
    description: The sub-RPE deposits are what ophthalmoscopy sees as drusen-like lesions.
    evidence:
    - reference: PMID:28847738
      reference_title: Sorsby fundus dystrophy - A review of pathology and disease mechanisms.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "ophthalmoscopy reveals accumulation of protein/lipid deposits under the retinal pigment epithelium (RPE), referred to as drusen, in the eyes of patients with SFD"
      explanation: Identifies the clinically visible drusen with the sub-RPE deposit.
  - target: Yellow/white macular and retinal lesions
    causal_link_type: DIRECT
  - target: Reticular pseudodrusen
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reticular pseudodrusen are subretinal rather than sub-RPE, and their
      association with SFD is read as implicating Bruch's membrane or its
      interface with the RPE rather than as a direct consequence of the deposit.
    evidence:
    - reference: PMID:26077580
      reference_title: Reticular Pseudodrusen in Sorsby Fundus Dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The association of RPD with SFD implicates a role of Bruch's membrane, the Bruch's membrane-retinal pigment epithelium interface, or both in the pathogenesis of RPD."
      explanation: The authors state the inferred relation between the membrane lesion and pseudodrusen without a defined mechanism.
  - target: Abnormal indocyanine green angiography
    causal_link_type: DIRECT
- name: Impaired Transport Across Bruch's Membrane
  description: >-
    The thickened membrane and its deposits reduce metabolic exchange between
    the choroid and the outer retina. The hypothesis tested clinically was that
    the barrier locally deprives photoreceptors of vitamin A, and the reversal of
    night blindness by oral vitamin A within a week supports it.
  biological_scale: TISSUE
  locations:
  - preferred_term: Bruch's membrane
    term:
      id: UBERON:0003957
      label: Bruch's membrane
  biological_processes:
  - preferred_term: retinol transport to the photoreceptors
    term:
      id: GO:0034633
      label: retinol transport
    modifier: DECREASED
  evidence:
  - reference: PMID:7550309
    reference_title: Night blindness in Sorsby's fundus dystrophy reversed by vitamin A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a SFD family with a novel TIMP3 point mutation, we tested a hypothesis that their night blindness is due to a chronic deprivation of vitamin A at the level of the photoreceptors caused by a thickened membrane barrier between the photoreceptor layer and its blood supply."
    explanation: States the barrier hypothesis that the same study then tested by supplementation.
  downstream:
  - target: Photoreceptor Vitamin A Deprivation
    causal_link_type: DIRECT
    description: >-
      Restoring the supply by high oral doses abolishes the functional deficit,
      which is the clinical evidence that the barrier deprives photoreceptors of
      vitamin A.
    evidence:
    - reference: PMID:7550309
      reference_title: Night blindness in Sorsby's fundus dystrophy reversed by vitamin A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Nutritional night blindness is thus part of the pathophysiology of this genetic disease and vitamin A supplementation can lead to dramatic restoration of photoreceptor function."
      explanation: >-
        The response to supplementation is the authors' basis for calling the
        deficiency nutritional; the deprivation itself was not measured, so the
        quote supports the step by inference from the therapeutic result.
- name: Photoreceptor Vitamin A Deprivation
  description: >-
    Local deficiency of vitamin A at the photoreceptors slows rhodopsin
    regeneration and so delays rod-mediated dark adaptation. Scotopic thresholds
    are elevated and the rod portion of the dark adaptation curve is prolonged in
    retinal regions carrying the deposit, while ophthalmoscopically normal
    regions are affected minimally; rod-mediated dark adaptation can nonetheless
    be slowed before any change is visible on multimodal imaging.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: dark adaptation
    term:
      id: GO:1990603
      label: dark adaptation
    modifier: DECREASED
  - preferred_term: retinoid metabolic process
    term:
      id: GO:0001523
      label: retinoid metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:1559761
    reference_title: Abnormal dark adaptation and rhodopsin kinetics in Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In retinal regions with the yellow deposit, scotopic thresholds were elevated, the rod-cone break was delayed or indistinct, the time courses for the rod portion of the dark adaptation curve was prolonged, and rhodopsin regeneration was slow in the one patient in whom measurements were made."
    explanation: Measures the rod functional deficit and its co-location with the deposit.
  - reference: PMID:1559761
    reference_title: Abnormal dark adaptation and rhodopsin kinetics in Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In regions of ophthalmoscopically normal retina, dark adaptation was affected minimally, and in one patient, rhodopsin was regenerated at a normal rate."
    explanation: The regional correspondence between deposit and deficit supports a local rather than systemic cause.
  - reference: PMID:34352251
    reference_title: Visual Dysfunction and Structural Correlates in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with SFD exhibit severely impaired scotopic visual function even in the absence of funduscopic alterations on multimodal imaging."
    explanation: A prospective study of 16 patients and 20 controls found severely impaired rod-driven function, present before any fundus change.
  - reference: PMID:9286267
    reference_title: Rod plateaux during dark adaptation in Sorsby's fundus dystrophy and vitamin A deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "In the patient with VAD, vitamin A supplementation led to accelerated recovery and disappearance of the transitory rod plateaux."
    explanation: >-
      This study measured the same transitory rod plateaux in SFD and in
      systemic vitamin A deficiency; the quoted result is from the deficiency
      patient, so it supports the vitamin A reading of the SFD finding by
      analogy rather than directly.
  downstream:
  - target: Nyctalopia
    causal_link_type: DIRECT
    description: Slowed rod dark adaptation presents as night blindness.
    evidence:
    - reference: PMID:7550309
      reference_title: Night blindness in Sorsby's fundus dystrophy reversed by vitamin A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Within a week, the night blindness disappeared in patients at early stages of disease."
      explanation: Correcting the vitamin A supply removes the symptom, which links the two.
- name: Impaired TIMP-3 Inhibition of VEGFR2
  description: >-
    Wild-type TIMP-3 blocks VEGF binding to VEGF receptor-2 and so inhibits
    angiogenesis, a function of the C-terminal domain and independent of its
    metalloproteinase inhibition. Dimerized mutant protein inhibits the receptor
    much less well. For the Ser156Cys allele, endothelial cells expressing the
    mutant protein bind more VEGF and show increased VEGF-dependent migration and
    tube formation, with more membrane-associated VEGFR-2 in mutant mouse
    endothelium and in human SFD eyes.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: vascular endothelial growth factor receptor-2 signaling
    term:
      id: GO:0036324
      label: vascular endothelial growth factor receptor-2 signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:12652295
    reference_title: "A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TIMP3 blocks the binding of VEGF to VEGF receptor-2 and inhibits downstream signaling and angiogenesis."
    explanation: Establishes the wild-type function whose impairment this node describes.
  - reference: PMID:12652295
    reference_title: "A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This property seems to be independent of its MMP-inhibitory activity, indicating a new function for this molecule."
    explanation: Supports treating the VEGFR2 arm as separable from the metalloproteinase-inhibition arm.
  - reference: PMID:19478078
    reference_title: S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we report that expression of S156C TIMP-3 mutation in endothelial cells results in an abnormal localization of the protein, increased glycosylation, decreased matrix metalloproteinase inhibitory activity, and increased vascular endothelial growth factor (VEGF) binding with a consequent increase in VEGF-dependent migration and tube formation."
    explanation: Shows the pro-angiogenic consequence of the mutant protein in endothelial cells.
  - reference: PMID:19478078
    reference_title: S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These enhanced signaling events appear to be mediated as a consequence of a post-transcriptionally regulated increase in the expression of membrane-associated VEGFR-2 in endothelial cells of Timp-3(156/156) mutant mice as well as in human Sorsby fundus dystrophy eyes."
    explanation: >-
      Graded on the human half of the quoted finding, increased
      membrane-associated VEGFR-2 in human SFD eyes; the same sentence reports
      the mouse result, which is cited separately in the animal model record.
  downstream:
  - target: Choroidal Neovascular Membrane Formation
    causal_link_type: DIRECT
    description: >-
      Loss of restraint on VEGFR2 is the proposed route to the neovascular
      membranes that characterize the disease.
    evidence:
    - reference: PMID:37013036
      reference_title: Evidence that all Sorsby's fundus dystrophy mutations cause TIMP3 dimerization resulting in impaired inhibition of VEGFR2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "This led us to hypothesize that dimerization of TIMP3 about the carboxyl domain may impair the ability of all mutant TIMP3 proteins to inhibit VEGFR2, potentially explaining the CNV which is a hallmark of this disease."
      explanation: >-
        The receptor-inhibition defect was measured in cell assays; its
        attribution to the neovascularization seen in patients is the authors'
        inference from it.
- name: Increased MMP2 Activity and bFGF Release
  description: >-
    In the Timp3 S179C knock-in mouse, reduced metalloproteinase inhibition
    raises MMP2 activity and basic fibroblast growth factor levels, mutant RPE
    cells secrete more bFGF, and conditioned medium from them drives endothelial
    angiogenesis. This is a second, VEGF-independent route to neovascularization;
    the mouse work is the principal source, and the equivalent human measurement
    has not been reported.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: fibroblast growth factor receptor signaling pathway
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:31757977
    reference_title: Sorsby Fundus Dystrophy Mutation in Tissue Inhibitor of Metalloproteinase 3 (TIMP3) promotes Choroidal Neovascularization via a Fibroblast Growth Factor-dependent Mechanism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "S179C mutant-TIMP3 in retinal pigment epithelial (RPE) cells showed increased secretion of bFGF and conditioned medium from these cells induced increased angiogenesis in endothelial cells."
    explanation: Mutant RPE cells secrete more bFGF and their medium is pro-angiogenic.
  downstream:
  - target: Choroidal Neovascular Membrane Formation
    causal_link_type: DIRECT
    description: >-
      The authors propose an FGFR-1-dependent route from the mutant protein to
      neovascularization, alongside the VEGFR2 route.
    evidence:
    - reference: PMID:31757977
      reference_title: Sorsby Fundus Dystrophy Mutation in Tissue Inhibitor of Metalloproteinase 3 (TIMP3) promotes Choroidal Neovascularization via a Fibroblast Growth Factor-dependent Mechanism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These studies suggest that S179C-TIMP3 may promote angiogenesis and CNV via a FGFR-1-dependent pathway by increasing bFGF release and activity."
      explanation: States the proposed FGF-dependent route, established in the mouse and in cell culture.
- name: Choroidal Neovascular Membrane Formation
  description: >-
    New vessels grow from the choroid through Bruch's membrane under the retina,
    with subretinal hemorrhage and exudation, and organize into a disciform
    macular scar. The median age at onset in the first eye was 46.1 years in a
    42-patient Ser181Cys cohort, and the second eye followed on average 4.5 years
    later. Polypoidal choroidal neovascularization also occurs. This is the main
    cause of blindness in the disease, and the lesion that anti-VEGF therapy
    addresses.
  biological_scale: TISSUE
  locations:
  - preferred_term: capillary layer of choroid
    term:
      id: UBERON:0005336
      label: capillary layer of choroid
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: choroidal angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: INCREASED
  evidence:
  - reference: PMID:18501328
    reference_title: Clinical course and treatment outcomes of Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main cause of blindness resulting from this dystrophy is CNV."
    explanation: A 42-patient cohort identifies neovascularization as the main cause of blindness.
  - reference: PMID:18501328
    reference_title: Clinical course and treatment outcomes of Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age at onset of CNV in the first eye was 46.1 years and in the second eye was 50.3 years."
    explanation: Gives the age of onset in each eye in that cohort.
  downstream:
  - target: Choroidal neovascularization
    causal_link_type: DIRECT
    description: >-
      The neovascular membrane is what is seen and treated clinically as
      choroidal neovascularization.
  - target: Subretinal hemorrhage
    causal_link_type: DIRECT
  - target: Disciform macular scar
    causal_link_type: DIRECT
    description: The neovascular lesion organizes into subretinal fibrosis and a disciform scar.
    evidence:
    - reference: PMID:23099917
      reference_title: Ranibizumab for the management of Sorsby fundus dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Despite a single session of verteporphin photodynamic treatment in November 2007, the lesion relentlessly progressed to a disciform scar."
      explanation: Follows an untreated then photodynamically treated neovascular lesion to a disciform scar in one eye.
  - target: Polypoidal choroidal vasculopathy
    causal_link_type: DIRECT
  - target: Metamorphopsia
    causal_link_type: DIRECT
  - target: Progressive central vision loss
    causal_link_type: DIRECT
    description: >-
      Vision falls to 20/200 or below within a couple of years of neovascular
      onset in untreated eyes.
    evidence:
    - reference: PMID:18501328
      reference_title: Clinical course and treatment outcomes of Sorsby fundus dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The median age at which vision fell to 20/200 or below was 48 years (first eye) and 54 years (second eye)."
      explanation: Sets the loss of central acuity about two years after the median age of neovascular onset in the same cohort.
- name: Choriocapillaris Flow Impairment
  description: >-
    Flow signal deficits in the choriocapillaris are pronounced in early disease,
    extend beyond the areas of sub-RPE deposit, and track with thinning of the
    overlying photoreceptor layers. Choroidal thickness is a structural
    correlate of the deficit, whereas the thickness of the RPE-drusen complex is
    not.
  biological_scale: TISSUE
  locations:
  - preferred_term: capillary layer of choroid
    term:
      id: UBERON:0005336
      label: capillary layer of choroid
  evidence:
  - reference: PMID:34844251
    reference_title: Choriocapillaris Flow Signal Impairment in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with early SFD exhibit pronounced abnormalities of CC flow signal on OCTA, which are not limited to areas of sub-RPE deposits seen on OCT imaging."
    explanation: A case-control study of 18 eyes finds pronounced choriocapillaris flow abnormality in early disease.
  - reference: PMID:34844251
    reference_title: Choriocapillaris Flow Signal Impairment in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, analysis of the CC flow may enable clinical trials at earlier disease stages in SFD."
    explanation: The authors read the flow deficit as an early-stage disease measure, which is what places this node upstream of degeneration.
  downstream:
  - target: Photoreceptor and RPE Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Flow deficit density is associated with thinning of the overlying
      photoreceptor layers; the association is cross-sectional, so the direction
      of causation is not established by it.
    evidence:
    - reference: PMID:34844251
      reference_title: Choriocapillaris Flow Signal Impairment in Sorsby Fundus Dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The CC FD density was associated with an altered microstructure of the overlying photoreceptors (outer segments, inner segments, and outer nuclear layer thinning of -0.19 μm, -0.08 μm and -0.30 μm per %FD, respectively, all p < 0.001)."
      explanation: An association in a cross-sectional case-control study, which supports the step only by inference.
- name: RPE Glucose and Glutamine Metabolic Dysregulation
  description: >-
    RPE carrying a disease-associated TIMP3 variant uses more glucose and runs
    a higher glycolytic flux, shown by isotopic tracing in mutant ARPE-19 cells
    and in patient-derived iPSC-RPE, with altered malic enzyme activity on
    glutamine tracing. Because the RPE supplies glucose to the outer retina,
    the authors read this as a contributor to degeneration rather than as a
    bystander finding; it is a recent result and the step from metabolic change
    to cell loss is not yet demonstrated in this disease.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: glycolysis in the retinal pigment epithelium
    term:
      id: GO:0006096
      label: glycolytic process
    modifier: INCREASED
  - preferred_term: glutamine metabolism
    term:
      id: GO:0006541
      label: L-glutamine metabolic process
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:39047907
    reference_title: Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Stable isotope tracing experiments with ... glucose demonstrated enhanced glucose utilization and glycolytic activity in S179C TIMP3 APRE-19 cells."
    explanation: Isotopic tracing measures the raised glycolytic flux in mutant RPE-derived cells.
  - reference: PMID:39047907
    reference_title: Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Additionally, ... glutamine tracing found evidence of altered malic enzyme activity."
    explanation: Glutamine tracing in patient-derived RPE shows the second metabolic change this node records.
  - reference: PMID:39047907
    reference_title: Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This study provides important information on the dysregulation of RPE glucose metabolism in SFD and implicates a potential commonality with other retinal degenerative diseases, emphasizing RPE cellular metabolism as a therapeutic target."
    explanation: The authors' own statement of what the finding establishes, which stops short of a demonstrated route to cell loss.
- name: Increased RPE Susceptibility to Oxidative Stress
  description: >-
    RPE carrying a disease-associated Timp3 variant is more vulnerable to
    oxidative insult. Antioxidant genes are raised at baseline in mutant mouse
    RPE, and doses of sodium iodate that do not affect wild-type mice degenerate
    the mutant RPE and photoreceptors. Patient-derived RPE has lower reduced
    glutathione and is likewise more vulnerable. This is a second route to RPE
    loss, independent of neovascularization.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34929159
    reference_title: Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Finally, SFD RPE cells have decreased intracellular reduced glutathione and were found to be more vulnerable to oxidative stress."
    explanation: Patient-derived RPE is depleted of reduced glutathione and more vulnerable to oxidative stress.
  downstream:
  - target: Photoreceptor and RPE Degeneration
    causal_link_type: DIRECT
    description: >-
      Under low-dose oxidative insult the mutant RPE and photoreceptors
      degenerate where wild-type tissue does not.
    evidence:
    - reference: PMID:32828705
      reference_title: The retinal pigment epithelium in Sorsby Fundus Dystrophy shows increased sensitivity to oxidative stress-induced degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The RPE and photoreceptors in Timp3 mutant mice degenerated at low doses of sodium iodate, which had no effect in wildtype control mice."
      explanation: A controlled challenge in the knock-in mouse produces RPE and photoreceptor degeneration.
- name: Photoreceptor and RPE Degeneration
  description: >-
    Progressive atrophy of the retinal pigment epithelium, the photoreceptors and
    the choriocapillaris spreads from the posterior pole toward the periphery,
    giving geographic atrophy and finally widespread chorioretinal atrophy with
    fibrosis and choroidal thinning. Severe vision loss can occur by this route
    without any neovascular membrane.
  biological_scale: TISSUE
  locations:
  - preferred_term: macula
    term:
      id: UBERON:0000054
      label: macula
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  evidence:
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Late disease manifestations were uniform with widespread chorioretinal atrophy, fibrosis, and choroidal thinning."
    explanation: Describes the end-stage atrophic picture across three families.
  - reference: PMID:7920634
    reference_title: Sorsby's fundus dystrophy is genetically linked to chromosome 22q13-qter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Patients lose central vision from subretinal neovascularization and atrophy of the choriocapillaris, pigment epithelium and retina."
    explanation: Names both routes to central vision loss, the neovascular and the atrophic.
  downstream:
  - target: Chorioretinal atrophy
    causal_link_type: DIRECT
  - target: Macular geographic atrophy
    causal_link_type: DIRECT
    description: Rapidly progressive geographic atrophy is part of the ocular phenotype.
    evidence:
    - reference: PMID:25766588
      reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The ocular phenotype included drusen-like deposits, rapidly progressive geographic atrophy, choroidal neovascularization (CNV), and polypoidal choroidal neovascularization (PCV)."
      explanation: Lists geographic atrophy among the phenotype features of the studied families.
  - target: Choriocapillaris atrophy
    causal_link_type: DIRECT
  - target: Central scotoma
    causal_link_type: DIRECT
  - target: Progressive central vision loss
    causal_link_type: DIRECT
    description: >-
      Atrophy alone can take vision to a severe level without a neovascular
      membrane.
    evidence:
    - reference: PMID:31415707
      reference_title: Late-Stage Sorsby Fundus Dystrophy Manifesting Severe Vision Loss in the Absence of Choroidal Neovascularization.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although SFD is classically associated with CNV and subretinal fibrosis, some cases follow an atrophic course in the absence of CNV formation."
      explanation: A case with molecularly confirmed disease and atrophy but no neovascularization, which is why this edge is drawn separately from the neovascular one.
phenotypes:
- name: Nyctalopia
  category: Ophthalmological
  description: >-
    Night blindness with delayed rod-mediated dark adaptation, often an early or
    presenting symptom and reversible with high-dose vitamin A at early stages.
    Orphanet records it as frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Night blindness
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:30668888
    reference_title: The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Typical manifestations include night blindness, scotoma, and metamorphopsia with subsequent reduced central, detailed vision and color vision problems"
    explanation: Names night blindness among the typical manifestations of the disease.
  - reference: ORPHA:59181
    reference_title: Sorsby fundus dystrophy
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000662 | Nyctalopia | Frequent (79-30%)"
    explanation: Orphanet's HPO annotation records nyctalopia as frequent in this disease.
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.Tyr174Cys mutation carriers had first symptoms at approximately the third decade with dark adaptation problems and visual field defects."
    explanation: In one family dark adaptation problems were the presenting symptom, in the third decade.
- name: Drusen-like sub-RPE deposits
  category: Ophthalmological
  diagnostic: true
  description: >-
    Protein and lipid deposits beneath the retinal pigment epithelium, seen on
    ophthalmoscopy as drusen-like lesions distributed throughout the fundus
    rather than confined to the macula. Orphanet records subretinal deposits as
    very frequent.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Drusen-like deposits
    term:
      id: HP:0011510
      label: Drusen
  evidence:
  - reference: PMID:28847738
    reference_title: Sorsby fundus dystrophy - A review of pathology and disease mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "ophthalmoscopy reveals accumulation of protein/lipid deposits under the retinal pigment epithelium (RPE), referred to as drusen, in the eyes of patients with SFD"
    explanation: States the clinical finding and its sub-RPE location.
  - reference: PMID:30668888
    reference_title: The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The disease is characterized by thickening of the Bruch membrane, chorioretinal atrophy, and multiple drusen‐like deposits throughout the entire fundus."
    explanation: Gives the fundus-wide distribution of the deposits.
  - reference: ORPHA:59181
    reference_title: Sorsby fundus dystrophy
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031528 | Subretinal deposits | Very frequent (99-80%)"
    explanation: Orphanet records deposits as very frequent in this disease.
- name: Yellow/white macular and retinal lesions
  category: Ophthalmological
  description: >-
    White to yellow fundus spots at the level of Bruch's membrane, which the
    earliest clinical series were careful to distinguish from ordinary drusen.
    Orphanet records yellow/white macular lesions as very frequent.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Yellow/white macular lesion
    term:
      id: HP:0030500
      label: Yellow/white macular lesion
  evidence:
  - reference: PMID:2695876
    reference_title: Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in the first and most common, white to yellow fundus spots (which are not drusen) accompany a disciform macular degeneration"
    explanation: Describes the yellow/white fundus lesions in a seven-generation pedigree.
  - reference: ORPHA:59181
    reference_title: Sorsby fundus dystrophy
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030500 | Yellow/white lesions of the macula | Very frequent (99-80%)"
    explanation: Orphanet records the lesions as very frequent.
- name: Reticular pseudodrusen
  category: Ophthalmological
  description: >-
    Subretinal reticular deposits, most abundant in the superior quadrant and
    sparing the fovea, found frequently in patients in the sixth decade and
    absent in the youngest and oldest patients of the studied series. They are
    bound to subretinal deposits rather than to a drusen term because they lie
    above the RPE.
  phenotype_term:
    preferred_term: Reticular pseudodrusen
    term:
      id: HP:0031528
      label: Subretinal deposits
  evidence:
  - reference: PMID:26077580
    reference_title: Reticular Pseudodrusen in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reticular pseudodrusen were identified frequently in SFD patients in the sixth decade of life (5 of 7 [71%]) and were absent in younger (n = 3) or older (n = 6) patients."
    explanation: Gives the prevalence and age dependence in 16 patients from four families.
  - reference: PMID:26077580
    reference_title: Reticular Pseudodrusen in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They appeared as subretinal deposits on SD OCT imaging."
    explanation: Locates the lesions above the RPE, which is what the bound term asserts.
- name: Abnormal indocyanine green angiography
  category: Ophthalmological
  diagnostic: true
  description: >-
    Characteristically reduced fluorescence on late-phase indocyanine green
    angiography, present in asymptomatic young variant carriers whose
    funduscopy and other retinal imaging are normal, and more pronounced at
    later stages. Proposed as an early identifier of individuals at risk.
  phenotype_term:
    preferred_term: Reduced late-phase indocyanine green fluorescence
    term:
      id: HP:0030605
      label: Abnormal indocyanine green angiography
  evidence:
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three asymptomatic young carriers of a TIMP3 mutation with otherwise normal findings on funduscopy and retinal imaging showed a characteristically reduced fluorescence on late-phase ICG-A images."
    explanation: Documents the sign in asymptomatic carriers with otherwise normal imaging.
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This phenotypic sign was more pronounced and widespread in later disease stages."
    explanation: The sign becomes more marked with disease stage.
- name: Choroidal neovascularization
  category: Ophthalmological
  diagnostic: true
  description: >-
    Neovascular membranes grow from the choroid beneath the retina, typically
    presenting with sudden distortion or loss of central vision in the fourth to
    fifth decade, and are the main cause of blindness in the disease. The second
    eye follows on average 4.5 years after the first. Orphanet records
    choroidal neovascularization as frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Choroidal neovascularization
    term:
      id: HP:0011506
      label: Choroidal neovascularization
  evidence:
  - reference: PMID:18501328
    reference_title: Clinical course and treatment outcomes of Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean interval between the development of CNV in the first and second eye was 4.5 years."
    explanation: Gives the interval between eyes in a 42-patient cohort.
  - reference: ORPHA:59181
    reference_title: Sorsby fundus dystrophy
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011506 | Choroidal neovascularization | Frequent (79-30%)"
    explanation: Orphanet records choroidal neovascularization as frequent.
  - reference: PMID:27601084
    reference_title: A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "SFD is characterized by bilateral deposition of yellow drusen-like material and extensive choroidal neovascularization (CNV) occurring between the third to fifth decades of life."
    explanation: Gives the bilateral character and the decade of onset.
- name: Polypoidal choroidal vasculopathy
  category: Ophthalmological
  description: >-
    Polypoidal neovascular lesions occur alongside conventional choroidal
    neovascularization and widen the recognized TIMP3 phenotype.
  phenotype_term:
    preferred_term: Polypoidal choroidal neovascularization
    term:
      id: HP:0025569
      label: Polypoidal choroidal vasculopathy
  evidence:
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ocular phenotype included drusen-like deposits, rapidly progressive geographic atrophy, choroidal neovascularization (CNV), and polypoidal choroidal neovascularization (PCV)."
    explanation: Reports polypoidal lesions among the phenotype of three SFD families.
- name: Subretinal hemorrhage
  category: Ophthalmological
  description: >-
    Bleeding beneath the retina from the neovascular membrane, with macular
    hemorrhage capable of taking vision to 6/60 within months. The historical
    name hemorrhagic macular dystrophy records this feature.
  phenotype_term:
    preferred_term: Subretinal hemorrhage
    term:
      id: HP:0025243
      label: Subretinal hemorrhage
  evidence:
  - reference: "CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z"
    reference_title: TIMP3 / Sorsby fundus dystrophy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "affected individuals present with a range of clinical features including yellow/white lesions of the retina, nyctalopia, progressive loss of central vision, disciform macular scar, central scotoma, retinal exudate, subretinal hemorrhage, atrophy of the retina / choriocapillaris / retinal pigment epithelium, and choroidal neovascularization (CNV)"
    explanation: The ClinGen evidence summary lists subretinal hemorrhage among the clinical features of the disease.
  - reference: PMID:23099917
    reference_title: Ranibizumab for the management of Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in October 2007, an extensive macular hemorrhage developed with vision dropping to 6/60"
    explanation: A case in which macular hemorrhage from the neovascular lesion dropped acuity to 6/60.
- name: Disciform macular scar
  category: Ophthalmological
  description: >-
    Subretinal fibrosis organizing into a disciform scar is the end state of an
    untreated neovascular lesion, and the natural history of the disease
    involves early lesion fibrosis.
  phenotype_term:
    preferred_term: Disciform macular scar
    term:
      id: HP:0025094
      label: Disciform macular scar
  evidence:
  - reference: PMID:23099917
    reference_title: Ranibizumab for the management of Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The natural history of the condition involves early development of lesion fibrosis."
    explanation: States that fibrosis of the neovascular lesion occurs early in the untreated course.
  - reference: "CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z"
    reference_title: TIMP3 / Sorsby fundus dystrophy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "disciform macular scar, central scotoma, retinal exudate"
    explanation: The ClinGen evidence summary lists disciform macular scar among the clinical features.
- name: Metamorphopsia
  category: Ophthalmological
  description: >-
    Distortion of central vision, often the presenting symptom of a neovascular
    lesion and in two families the first symptom at around the sixth decade.
  phenotype_term:
    preferred_term: Metamorphopsia
    term:
      id: HP:0012508
      label: Metamorphopsia
  evidence:
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In families with p.Tyr177Cys and p.Tyr182Cys, metamorphopsia and/or decrease in visual acuity were the initial symptoms occurring at approximately the sixth decade of life."
    explanation: Metamorphopsia was an initial symptom in two of the three studied families.
  - reference: PMID:30668888
    reference_title: The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Typical manifestations include night blindness, scotoma, and metamorphopsia with subsequent reduced central, detailed vision and color vision problems"
    explanation: Lists metamorphopsia among the typical manifestations.
- name: Central scotoma
  category: Ophthalmological
  description: >-
    Loss of the central field, following macular atrophy or scarring. Orphanet
    records a large central visual field defect as frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Central scotoma
    term:
      id: HP:0000603
      label: Central scotoma
  evidence:
  - reference: "CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z"
    reference_title: TIMP3 / Sorsby fundus dystrophy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "disciform macular scar, central scotoma, retinal exudate"
    explanation: The ClinGen evidence summary lists central scotoma among the clinical features.
  - reference: ORPHA:59181
    reference_title: Sorsby fundus dystrophy
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "HP:0001129 | Large central visual field defect | Frequent (79-30%)"
    explanation: >-
      Orphanet records a large central visual field defect as frequent; the
      frequency band here is taken from that row, which names a broader class
      than the central scotoma the clinical sources describe.
- name: Progressive central vision loss
  category: Ophthalmological
  description: >-
    Loss of central vision in the fourth or fifth decade, by neovascularization
    or by macular atrophy, progressing to blindness in untreated disease;
    peripheral vision is lost later. Orphanet records visual loss as very
    frequent.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Progressive loss of central vision
    term:
      id: HP:0000529
      label: Progressive visual loss
  evidence:
  - reference: PMID:8981947
    reference_title: "Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Sorsby fundus dystrophy (SFD) originally was characterized as an autosomal dominant disorder in which patients lose central vision during the 4th or 5th decade of life."
    explanation: Gives the decade in which central vision is lost.
  - reference: ORPHA:59181
    reference_title: Sorsby fundus dystrophy
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000572 | Visual loss | Very frequent (99-80%)"
    explanation: Orphanet records visual loss as very frequent.
  - reference: PMID:34070857
    reference_title: "Visual Outcome after Intravitreal Anti-VEGF Therapy for Macular Neovascularisation Secondary to Sorsby's Fundus Dystrophy: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "leading to severe bilateral vision loss and blindness if left untreated"
    explanation: States the untreated outcome, which is what the treatment section is measured against.
- name: Chorioretinal atrophy
  category: Ophthalmological
  description: >-
    Atrophy of the retina, retinal pigment epithelium and choroid, spreading
    from the posterior pole toward the periphery and uniform in late disease.
  phenotype_term:
    preferred_term: Chorioretinal atrophy
    term:
      id: HP:0000533
      label: Chorioretinal atrophy
  evidence:
  - reference: PMID:2695876
    reference_title: Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atrophy of the retina, pigment epithelium, and choroid then slowly progresses toward the periphery."
    explanation: Describes the spread of atrophy in a seven-generation pedigree.
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Late disease manifestations were uniform with widespread chorioretinal atrophy, fibrosis, and choroidal thinning."
    explanation: Records widespread chorioretinal atrophy as the uniform late manifestation.
- name: Macular geographic atrophy
  category: Ophthalmological
  description: >-
    Rapidly progressive geographic atrophy of the retinal pigment epithelium in
    the macula, which can take vision to a severe level without any neovascular
    membrane.
  phenotype_term:
    preferred_term: Macular geographic atrophy
    term:
      id: HP:0031609
      label: Macular geographic atrophy
  evidence:
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ocular phenotype included drusen-like deposits, rapidly progressive geographic atrophy, choroidal neovascularization (CNV), and polypoidal choroidal neovascularization (PCV)."
    explanation: Lists rapidly progressive geographic atrophy in the phenotype of three families.
  - reference: PMID:32828705
    reference_title: The retinal pigment epithelium in Sorsby Fundus Dystrophy shows increased sensitivity to oxidative stress-induced degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Patients with SFD present with pathophysiology similar to the more common Age-related Macular Degeneration (AMD) and loss of vision due to both choroidal neovascularization and geographic atrophy."
    explanation: Names geographic atrophy as one of the two routes to vision loss.
- name: Choriocapillaris atrophy
  category: Ophthalmological
  description: >-
    Atrophy of the choriocapillaris, preceded in early disease by measurable flow
    deficits on optical coherence tomography angiography. Orphanet records it as
    frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Choriocapillaris atrophy
    term:
      id: HP:0030491
      label: Choriocapillaris atrophy
  evidence:
  - reference: ORPHA:59181
    reference_title: Sorsby fundus dystrophy
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030491 | Choriocapillaris atrophy | Frequent (79-30%)"
    explanation: Orphanet records choriocapillaris atrophy as frequent.
  - reference: PMID:7920634
    reference_title: Sorsby's fundus dystrophy is genetically linked to chromosome 22q13-qter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Patients lose central vision from subretinal neovascularization and atrophy of the choriocapillaris, pigment epithelium and retina."
    explanation: Names choriocapillaris atrophy among the lesions that cost central vision.
- name: Emphysema
  category: Respiratory
  description: >-
    Severe emphysema without smoking or asthma was present in every affected
    person over 50 in one family carrying p.Tyr191Cys, and the second family of
    the same report had milder lung disease with bronchiectasis. Later reports
    found normal pulmonary function in affected individuals, so penetrance of
    the pulmonary feature appears variable; ClinGen records the recommendation
    that affected people avoid tobacco and have regular pulmonary examination.
    No frequency is recorded here: the feature is reported in two families and
    absent from pulmonary function testing in later reports, and no source gives
    a proportion.
  phenotype_term:
    preferred_term: Pulmonary emphysema
    term:
      id: HP:0002097
      label: Emphysema
  evidence:
  - reference: PMID:27601084
    reference_title: A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family 1, all SFD patients older than 50 (two generations) had also a severe emphysema, despite no history of smoking or asthma."
    explanation: Reports severe emphysema co-segregating with the eye disease in one family.
  - reference: "CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z"
    reference_title: TIMP3 / Sorsby fundus dystrophy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More recent reports have evaluated pulmonary function in affected individuals and found them to be normal, indicating that modifier genes and/or environmental exposures likely affect the penetrance of non-retinal features of Sorsby fundus dystrophy."
    explanation: The ClinGen summary records that the pulmonary feature is not consistently present, which is why no frequency is recorded.
genetic:
- name: TIMP3
  gene_term:
    preferred_term: TIMP3
    term:
      id: hgnc:11822
      label: TIMP3
  relationship_type: CAUSATIVE
  association: Causative
  variant_origin: GERMLINE
  features: >-
    Heterozygous TIMP3 variants cause the disease. The locus was mapped to
    22q13-qter by linkage in a single large family, and point mutations were then
    found in two SFD pedigrees. Reported alleles are predominantly missense and
    concentrated in exon 5, which encodes almost all of the C-terminal domain;
    most add or remove a cysteine, and the cysteine-altering alleles disturb the
    arrangement of twelve conserved cysteines and six disulfide bonds. Exceptions
    exist: His158Arg alters no cysteine, Ser38Cys lies in exon 1, one nonsense
    allele and one splice-acceptor allele are known, and variants in the
    N-terminal signal peptide give a phenotype the reporting authors treat as
    distinct. A Ser181Cys founder allele accounts for most British Isles
    families, with carriers in Canada, the United States and South Africa
    descending from the same ancestor, and Ser38Cys is a founder allele in
    Belgian and northern French families. A 2024 mechanistic review counts 21
    associated variants, of which a few have been studied in depth. The
    phenotype attached to the gene is still widening: a p.Tyr137Cys variant was
    found in a father and son first diagnosed with retinitis pigmentosa, so
    TIMP3 is worth considering in atypical pigmentary retinopathy.
  notes: >-
    Variant numbering in the names used here follows the secreted protein,
    excluding the 23-residue signal peptide. The same alleles appear in the
    literature under signal peptide-inclusive numbering: Ser156Cys as S179C,
    Ser181Cys as S204C, Tyr168Cys as Y191C.
  evidence:
  - reference: PMID:7920634
    reference_title: Sorsby's fundus dystrophy is genetically linked to chromosome 22q13-qter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recombinant chromosomes sublocalize the SFD gene to 22q13-qter between D22S275 and D22S274."
    explanation: Linkage analysis placed the locus in the interval that contains TIMP3.
  - reference: PMID:7894485
    reference_title: Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have now identified point mutations in the TIMP3 gene in affected members of two SFD pedigrees."
    explanation: The original gene identification.
  - reference: PMID:10854443
    reference_title: A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in Sorsby's fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Five different mutations have previously been identified, all introducing an extra cysteine residue into exon 5 (which forms part of the C-terminal domain) of the TIMP-3 molecule"
    explanation: Gives the exon and domain in which the early alleles sit and their shared cysteine effect.
  - reference: PMID:8919688
    reference_title: "Sorsby's fundus dystrophy in the British Isles: demonstration of a striking founder effect by microsatellite-generated haplotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of the same Ser181Cys mutation cosegregating with disease in each family led us to consider the hypothesis of a founder effect being present."
    explanation: The same allele in 15 apparently unrelated British Isles families indicates a founder effect.
  - reference: PMID:9400791
    reference_title: "Sorsby fundus dystrophy: reevaluation of variable expressivity in patients carrying a TIMP3 founder mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have extended previous findings on a Ser181Cys founder mutation in SFD families from the British Isles and show that carriers of this mutation residing in Canada, the United States, and South Africa likewise are descendants of the British ancestor"
    explanation: Extends the founder allele to families on three further continents.
  - reference: PMID:38601018
    reference_title: "Review: Mechanisms of TIMP-3 accumulation and pathogenesis in Sorsby fundus dystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "There are 21 mutations currently associated with SFD"
    explanation: Gives the size of the reported variant set as of the review.
  - reference: PMID:32715858
    reference_title: A novel TIMP3 mutation associated with a retinitis pigmentosa-like phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is important to consider mutations in TIMP3 in atypical cases of Retinitis Pigmentosa particularly in the absence of known variants."
    explanation: A father and son with a novel TIMP3 variant were first diagnosed with retinitis pigmentosa, which widens the phenotype attached to the gene.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: "CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z"
    evidence:
    - reference: "CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z"
      reference_title: TIMP3 / Sorsby fundus dystrophy (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "TIMP3 | HGNC:11822 | Sorsby fundus dystrophy | MONDO:0007640 | AD | Definitive"
      explanation: The ClinGen Retina Gene Curation Expert Panel classifies TIMP3 in Sorsby fundus dystrophy as Definitive for autosomal dominant inheritance.
  variants:
  - name: p.Ser181Cys
    synonyms:
    - S181C
    - p.Ser204Cys
    description: >-
      The British Isles founder allele, found in 15 genealogically unrelated
      families and in emigrant families in Canada, the United States and South
      Africa. It is the allele of the 42-patient natural-history cohort and of
      the donor eyes used for the histopathology.
    gene:
      preferred_term: TIMP3
      term:
        id: hgnc:11822
        label: TIMP3
    clinical_significance: PATHOGENIC
    type: missense_variant
    evidence:
    - reference: PMID:8919688
      reference_title: "Sorsby's fundus dystrophy in the British Isles: demonstration of a striking founder effect by microsatellite-generated haplotypes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This haplotype analysis has refined the TIMP3 gene localization to a 1- to 3-cM interval between marker loci D22S273 and D22S281 and provides strong evidence for a single mutational event being responsible for the majority of SFD identified in the British Isles."
      explanation: A single mutational event accounts for most British Isles disease.
    - reference: PMID:18501328
      reference_title: Clinical course and treatment outcomes of Sorsby fundus dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A cohort of 42 patients with the Ser181 Cys TIMP3 mutation were identified from the electronic database of genetic retinal diseases in Moorfields Eye Hospital."
      explanation: Identifies the cohort whose natural history and treatment outcomes this entry cites as carrying this allele.
  - name: p.Ser156Cys
    synonyms:
    - S156C
    - p.Ser179Cys
    description: >-
      Reported in a family with unusual clinical features, and the allele used
      for the knock-in mouse lines and for the endothelial and RPE cell work on
      VEGFR2 and bFGF. In cell assays it forms higher-molecular-weight complexes
      and shows reduced metalloproteinase inhibition with increased VEGF binding.
    gene:
      preferred_term: TIMP3
      term:
        id: hgnc:11822
        label: TIMP3
    clinical_significance: PATHOGENIC
    type: missense_variant
    evidence:
    - reference: PMID:12147610
      reference_title: A mouse model for Sorsby fundus dystrophy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To facilitate in vivo investigation of mutant TIMP3, the authors generated a knock-in mouse carrying a disease-related Ser156Cys mutation in the orthologous murine Timp3 gene."
      explanation: Names the allele as disease-related and the basis of the knock-in model.
    - reference: PMID:11827795
      reference_title: "Sorsby's fundus dystrophy tissue inhibitor of metalloproteinases-3 (TIMP-3) mutants have unimpaired matrix metalloproteinase inhibitory activities, but affect cell adhesion to the extracellular matrix."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Two of the mutants (Ser156Cys and Ser181Cys) showed a marked propensity to form multiple higher molecular-weight complexes that retained TIMP activity on reverse zymography."
      explanation: Documents the multimerization behaviour of this allele in cell culture.
  - name: p.Ser38Cys
    synonyms:
    - S38C
    - c.113C>G
    description: >-
      An exon 1 founder allele in Belgian and northern French families with
      late-onset disease. It is the clearest exception to the exon 5 rule: the
      reported mechanism is disruption of an established intramolecular
      disulfide bond and formation of a new one, rather than dimerization. The
      same allele was reported in a family with eye and lung disease.
    gene:
      preferred_term: TIMP3
      term:
        id: hgnc:11822
        label: TIMP3
    clinical_significance: PATHOGENIC
    type: missense_variant
    evidence:
    - reference: PMID:30668888
      reference_title: The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Haplotype reconstruction in three SFD families revealed that the identified c.113C>G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late-onset SFD phenotype."
      explanation: Establishes the allele as a founder mutation with a late-onset phenotype.
    - reference: PMID:30668888
      reference_title: The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We could not confirm a previous hypothesis on dimerization of mutant TIMP3 proteins."
      explanation: For this allele the dimerization model was not reproduced, which is why the entry records intramolecular bonding separately.
  - name: p.His158Arg
    synonyms:
    - H158R
    description: >-
      A late-onset allele and the first reported coding variant that does not
      create an unpaired cysteine; the residue is conserved across vertebrate
      TIMP homologs and modeling places it at a protein-protein interaction
      interface.
    gene:
      preferred_term: TIMP3
      term:
        id: hgnc:11822
        label: TIMP3
    clinical_significance: PATHOGENIC
    type: missense_variant
    evidence:
    - reference: PMID:16989765
      reference_title: A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A heterozygous His158Arg mutation was found in seven affected family members and was absent from an unaffected member and 98 unrelated controls."
      explanation: Segregation in seven affected members with absence from controls supports pathogenicity.
    - reference: PMID:16989765
      reference_title: A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Onset of disease occurred in the fifth to seventh decades of life."
      explanation: Gives the late onset in this family.
  - name: TIMP3 signal peptide variants
    synonyms:
    - L10H
    - G12R
    description: >-
      Variants in the N-terminal signal peptide reported in two families with
      early-onset diffuse maculopathy and no choroidal neovascularization. The
      reporting authors treat this as a phenotype distinct from classic Sorsby
      fundus dystrophy, with impaired signal peptide cleavage and defective
      extracellular deposition rather than accumulation of matrix-bound mutant
      protein. Recorded here as a variant class with that caveat, not as a
      subtype, because no separate disease concept exists for it.
    gene:
      preferred_term: TIMP3
      term:
        id: hgnc:11822
        label: TIMP3
    clinical_significance: PATHOGENIC
    type: missense_variant
    evidence:
    - reference: PMID:35679059
      reference_title: Early-Onset TIMP3-Related Retinopathy Associated With Impaired Signal Peptide.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Eleven individuals from 2 families with early-onset diffuse maculopathy without choroidal neovascularization harbor TIMP3 variants (L10H or G12R) in the N-terminal signaling peptide were analyzed."
      explanation: Identifies the variants and the families, and records the absence of neovascularization.
    - reference: PMID:35679059
      reference_title: Early-Onset TIMP3-Related Retinopathy Associated With Impaired Signal Peptide.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This study found that TIMP3 variants altering signal peptide function deviated from classic Sorsby fundus dystrophy both in phenotypic features and underlying mechanism."
      explanation: The authors' own statement that this group deviates from classic SFD, which is the caveat recorded here.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >-
    Autosomal dominant with penetrance reported as complete, and variable
    expressivity in age of onset and fundus appearance. A historically proposed
    autosomal recessive form rests on one consanguineous Finnish family; the
    same family was later shown to carry a heterozygous Gly166Cys TIMP3 variant
    in all affected members, which the authors read as dominant inheritance, and
    the ClinGen Retina GCEP records the recessive proposal as refuted. The
    MONDO descendant MONDO:0009918, the recessive pseudoinflammatory form
    (OMIM 264420), is therefore not curated as a subtype of this entry.
  evidence:
  - reference: PMID:36197222
    reference_title: "Sorsby fundus dystrophy (SFD): A narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Sorsby fundus dystrophy (SFD) is a rare autosomal dominant disorder with complete penetrance affecting the macula."
    explanation: A narrative review states autosomal dominant inheritance with complete penetrance.
  - reference: PMID:8981947
    reference_title: "Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel heterozygous Gly166Cys mutation in TIMP3 in all affected individuals and provide strong evidence for an autosomal dominant inheritance of the SFD phenotype in this family."
    explanation: Reinvestigation of the family that defined the recessive concept found a heterozygous variant segregating with disease.
  - reference: PMID:8981947
    reference_title: "Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considering all available data, we suggest that SFD is a genetically homogeneous, autosomal dominant condition."
    explanation: The authors' conclusion against a recessive mode of inheritance, which is the basis for leaving the recessive MONDO descendant out.
  - reference: "CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z"
    reference_title: TIMP3 / Sorsby fundus dystrophy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A proposed alternative mechanism of autosomal recessive inheritance of Sorsby fundus dystrophy that involved a consanguineous family and preceded mapping of the disease locus (PMID:7143944) was refuted by identification of a heterozygous TIMP3 variant specific to the affected family members (PMID:8981947)."
    explanation: ClinGen's own lumping and splitting assessment records the recessive proposal as refuted.
  - reference: PMID:7148944
    reference_title: Pseudoinflammatory fundus dystrophy with autosomal recessive inheritance.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "a mode of inheritance which is probably autosomal recessive"
    explanation: >-
      The original report of the Finnish family proposed recessive inheritance,
      the claim this block records as superseded; cited so that the concept
      behind MONDO:0009918 is traceable.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.45
  rate_denominator: POPULATION
  notes: >-
    From the estimate of 1 in 220,000 given in a review of the disease, which is
    0.45 per 100,000. Orphanet records its own point-prevalence class as unknown.
  evidence:
  - reference: PMID:28847738
    reference_title: Sorsby fundus dystrophy - A review of pathology and disease mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Sorsby fundus dystrophy (SFD) is an autosomal dominant macular dystrophy with an estimated prevalence of 1 in 220,000 and an onset of disease around the 4th to 6th decade of life."
    explanation: Gives the prevalence estimate this record normalizes.
  - reference: ORPHA:59181
    reference_title: Sorsby fundus dystrophy
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unknown | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet records the worldwide point-prevalence class as unknown.
progression:
- phase: Preclinical carrier stage
  notes: >-
    Variant carriers without symptoms already show thickening of Bruch's
    membrane and choriocapillaris thinning on optical coherence tomography
    angiography, and reduced late-phase indocyanine green fluorescence; rod
    dark adaptation can be slowed before any change is visible on multimodal
    imaging.
  evidence:
  - reference: PMID:35483032
    reference_title: SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY DETECTION OF BRUCH MEMBRANE AND CHORIOCAPILLARIS ABNORMALITIES IN SORSBY MACULAR DYSTROPHY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Swept-source optical coherence tomography angiography imaging can detect BM and CC abnormalities in vivo in subjects unaware of their TIMP3 status in a family with SMD."
    explanation: Structural change is detectable before clinical disease in carriers.
  - reference: PMID:34352251
    reference_title: Visual Dysfunction and Structural Correlates in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whereas RMDA could be slowed even in the absence of fundus alterations on multimodal imaging"
    explanation: Rod-mediated dark adaptation is abnormal before imaging shows fundus change.
- phase: Early symptomatic stage
  notes: >-
    Night blindness, dark adaptation difficulty and visual field defects appear
    first in some families, while in others metamorphopsia or reduced acuity is
    the presenting complaint. Best-corrected acuity can still be normal while
    scotopic function is already impaired.
  evidence:
  - reference: PMID:34352251
    reference_title: Visual Dysfunction and Structural Correlates in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to BCVA, scotopic visual function tests are suitable to quantify dysfunction in the early stages."
    explanation: Records that rod-driven function, not best-corrected acuity, is what is abnormal early.
- phase: Neovascular stage
  notes: >-
    Sudden central vision loss from a choroidal neovascular membrane, at a
    median of 46 years in the first eye and 50 years in the second in the
    Ser181Cys cohort, with vision falling to 20/200 or below about two years
    later if untreated.
  evidence:
  - reference: PMID:18501328
    reference_title: Clinical course and treatment outcomes of Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age at onset of CNV in the first eye was 46.1 years and in the second eye was 50.3 years."
    explanation: Gives the median ages of neovascular onset in each eye.
- phase: Atrophic end stage
  notes: >-
    Widespread chorioretinal atrophy, fibrosis and choroidal thinning, uniform
    across families in late disease, with loss first of central and then of
    peripheral vision.
  evidence:
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Late disease manifestations were uniform with widespread chorioretinal atrophy, fibrosis, and choroidal thinning."
    explanation: Describes the end-stage picture.
  - reference: ORPHA:59181
    reference_title: Sorsby fundus dystrophy
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "leading to loss of central vision, then peripheral vision, and eventually blindness"
    explanation: Orphanet's definition gives the order in which vision is lost.
diagnosis:
- name: Multimodal retinal imaging
  description: >-
    Optical coherence tomography shows irregular thickening of Bruch's membrane
    and the sub-RPE deposit; optical coherence tomography angiography shows
    choriocapillaris flow deficits and detects neovascular membranes; late-phase
    indocyanine green angiography shows reduced fluorescence, which has been
    proposed for identifying carriers at risk before symptoms; fundus
    autofluorescence is frequently abnormal, and reticular pseudodrusen
    appear on it as hypoautofluorescent lesions. Early neovascularization in a
    patient with no predisposing factor such as high myopia should prompt the
    diagnosis.
  diagnosis_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:27601084
    reference_title: A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite variable and confounding phenotypes, this dystrophy should be considered in patients with early neovascularization in absence of predisposing factors such as high myopia, or with irregular thickening of the Bruch membrane as shown on SD-OCT."
    explanation: States the two findings that should raise the diagnosis, and names the imaging modality.
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging using late-phase ICG-A may be useful for early identification of individuals at risk for developing SFD."
    explanation: Proposes late-phase indocyanine green angiography for early identification.
  - reference: ORPHA:59181
    reference_title: Sorsby fundus dystrophy
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030602 | Abnormal fundus autofluorescence imaging | Frequent (79-30%)"
    explanation: Orphanet records abnormal fundus autofluorescence as frequent, which is the basis for listing the modality here.
  - reference: PMID:26077580
    reference_title: Reticular Pseudodrusen in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reticular pseudodrusen were hyporeflective on NIR reflectance and hypofluorescent on fundus autofluorescence imaging."
    explanation: Gives the autofluorescence appearance of one of the lesions this entry records.
- name: TIMP3 molecular genetic testing
  description: >-
    Diagnosis is confirmed by finding a heterozygous TIMP3 variant. Testing is
    directed at exon 5 first, since most alleles lie there, but exon 1 and the
    signal peptide sequence carry reported variants too, so a negative exon 5
    result does not exclude the disease.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:23099917
    reference_title: Ranibizumab for the management of Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA analysis revealed the presence of mutation c.610A>T (p.Ser204Cys) in exon 5 of the TIMP3 gene and confirmed the diagnosis of Sorsby fundus dystrophy."
    explanation: Molecular testing confirmed the clinical diagnosis in a case.
  - reference: PMID:30668888
    reference_title: The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haplotype reconstruction in three SFD families revealed that the identified c.113C>G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late-onset SFD phenotype."
    explanation: An exon 1 founder allele, which is why testing cannot be confined to exon 5.
treatments:
- name: Intravitreal anti-VEGF therapy for choroidal neovascularization
  description: >-
    Intravitreal bevacizumab or ranibizumab is the mainstay for the neovascular
    complication. A systematic review of 31 cases found good responses when
    treatment began immediately after symptom onset, with the delay between
    first symptoms and treatment determining subretinal scar formation and
    functional prognosis; 11 of 20 eyes with acuity reported before and after
    treatment kept driving vision, while 5 worsened. A 12-year two-sister series
    found a treat-and-extend schedule better than pro re nata at preventing
    recurrence. The therapy addresses the neovascular lesion and not the
    underlying dystrophy, so atrophic progression continues.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bevacizumab
      term:
        id: NCIT:C2039
        label: Bevacizumab
    - preferred_term: ranibizumab
      term:
        id: NCIT:C67562
        label: Ranibizumab
  target_phenotypes:
  - preferred_term: Choroidal neovascularization
    term:
      id: HP:0011506
      label: Choroidal neovascularization
  target_mechanisms:
  - target: Choroidal Neovascular Membrane Formation
    treatment_effect: INHIBITS
    description: >-
      The agents neutralize VEGF in the vitreous and so suppress the neovascular
      lesion; they do not restore TIMP-3 function or clear the deposit.
    evidence:
    - reference: PMID:34070857
      reference_title: "Visual Outcome after Intravitreal Anti-VEGF Therapy for Macular Neovascularisation Secondary to Sorsby's Fundus Dystrophy: A Systematic Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In MNV secondary to SFD, the delay between first symptoms and access to anti-VEGF treatment determines subretinal scar formation and thereby, functional prognosis."
      explanation: The effect on the neovascular lesion and its visual consequence depends on how early the agent is given.
  evidence:
  - reference: PMID:34070857
    reference_title: "Visual Outcome after Intravitreal Anti-VEGF Therapy for Macular Neovascularisation Secondary to Sorsby's Fundus Dystrophy: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All papers in common, however, reported satisfied to excellent responses to anti-VEGF therapy if patients were diagnosed and treated immediately after onset of symptoms."
    explanation: Pooled across 14 publications and one further patient, outcomes were good with prompt treatment.
  - reference: PMID:34070857
    reference_title: "Visual Outcome after Intravitreal Anti-VEGF Therapy for Macular Neovascularisation Secondary to Sorsby's Fundus Dystrophy: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 20 eyes, for which visual acuity was reported before and after treatment, five worsened and seven improved by more than 1 line, whereas eight eyes maintained their function by end of the follow up, and 11 eyes (55%) maintained a driving vision (Snellen VA ≥ 0.5)."
    explanation: Gives the per-eye outcome distribution, including the eyes that worsened on treatment.
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with CNV or PCV showed a favorable response to therapy with intravitreally injected bevacizumab."
    explanation: Favourable responses to bevacizumab in patients with neovascular and polypoidal lesions.
  - reference: PMID:30421618
    reference_title: Evaluation of Pro-re-Nata (PRN) and Treat and Extend Bevacizumab treatment protocols in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A T&E protocol appears more effective compared to pro re nata protocol in minimizing recurrence of choroidal neovascularization with potential secondary scar formation or atrophy."
    explanation: Compares the two dosing schedules over 12 years in two sisters.
- name: High-dose oral vitamin A for night blindness
  description: >-
    Oral vitamin A at 50,000 IU/day abolished night blindness within a week in
    patients at early stages of disease, and high-dose supplementation markedly
    improved rod-mediated dark adaptation and dark-adapted thresholds in one
    patient followed longitudinally. It addresses the local nutritional
    deficiency produced by the thickened membrane, not the dystrophy, and is
    off-label; the evidence is a small family study and single-patient
    longitudinal data.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: vitamin A supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: vitamin A
      term:
        id: CHEBI:12777
        label: vitamin A
  target_phenotypes:
  - preferred_term: Night blindness
    term:
      id: HP:0000662
      label: Nyctalopia
  target_mechanisms:
  - target: Photoreceptor Vitamin A Deprivation
    treatment_effect: BYPASSES
    description: >-
      Raising systemic vitamin A overcomes the local deficiency created by the
      transport barrier, without altering the barrier itself.
    evidence:
    - reference: PMID:7550309
      reference_title: Night blindness in Sorsby's fundus dystrophy reversed by vitamin A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nutritional night blindness is thus part of the pathophysiology of this genetic disease and vitamin A supplementation can lead to dramatic restoration of photoreceptor function."
      explanation: Supplementation restores photoreceptor function, which is the bypass this link records.
  evidence:
  - reference: PMID:7550309
    reference_title: Night blindness in Sorsby's fundus dystrophy reversed by vitamin A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vitamin A at 50,000 IU/d was administered orally. Within a week, the night blindness disappeared in patients at early stages of disease."
    explanation: Gives the dose, the route and the response, and restricts it to early-stage disease.
  - reference: PMID:34352251
    reference_title: Visual Dysfunction and Structural Correlates in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After high-dose vitamin A supplementation, RMDA and DA thresholds improved markedly."
    explanation: Longitudinal data from one patient show improved rod-mediated dark adaptation after supplementation.
  - reference: PMID:34352251
    reference_title: Visual Dysfunction and Structural Correlates in Sorsby Fundus Dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Improvement of scotopic dysfunction after (off-label) high-dose vitamin A intake, as observed in one patient in our study, is compatible with the hypothesized local deficiency of vitamin A secondary to Bruch's membrane alterations."
    explanation: Records that the use is off-label and that the observation is from a single patient.
- name: Systemic anti-TNF-alpha therapy (single case report)
  description: >-
    One 35-year-old patient with aggressive bilateral macular neovascularization
    and p.Ser204Cys, who showed disease activity on intravitreal bevacizumab and
    was controlled on repeated intravitreal triamcinolone, had no signs of
    disease activity over 18 months of subcutaneous adalimumab. The authors
    propose that the TIMP3 variant raises local tumour necrosis factor alpha
    because TIMP-3 restrains its shedding by ADAM17. The rationale is untested
    for this patient's allele. The only measurement a 2024 mechanistic review
    reports is for a different allele, Ser179Cys (Ser156Cys in secreted-protein
    numbering), which inhibits ADAM17 as well as wild-type TIMP-3 does; the same
    review states that the other SFD mutants, Ser204Cys (Ser181Cys) among them,
    have not been profiled. Because the case for a TNF arm rests on one patient
    plus TIMP-3 biology measured outside the eye, the entry records the
    treatment and its single-patient evidence without a mechanism node or
    pathophysiology target, and holds the question open in the discussions
    section.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
  target_phenotypes:
  - preferred_term: Choroidal neovascularization
    term:
      id: HP:0011506
      label: Choroidal neovascularization
  evidence:
  - reference: PMID:34376817
    reference_title: Treatment of Sorsby fundus dystrophy with anti-tumor necrosis factor-alpha medication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of the high lifetime risk of complication, she was switched to subcutaneous adalimumab and in follow-up over 18 months had no signs of disease activity."
    explanation: The observed result in the single reported patient.
  - reference: PMID:34376817
    reference_title: Treatment of Sorsby fundus dystrophy with anti-tumor necrosis factor-alpha medication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is possible with the mutation in the gene for TIMP-3, abnormally high tissue levels of TNFα are produced in the eye."
    explanation: States the proposed rationale, in the authors' own conditional terms.
  - reference: PMID:38601018
    reference_title: "Review: Mechanisms of TIMP-3 accumulation and pathogenesis in Sorsby fundus dystrophy."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "showed that the Ser179Cys variant retained the ability to inhibit ADAM17, ADAMTS-4, and ADAMTS-5 to the same degree as wild-type TIMP-3."
    explanation: >-
      Bears against the proposed rationale only by inference: the measured
      allele is Ser179Cys (Ser156Cys), not the patient's Ser204Cys (Ser181Cys).
      It shows that at least one SFD allele keeps ADAM17 inhibition, so loss of
      that inhibition cannot be assumed to be common to the disease.
  - reference: PMID:38601018
    reference_title: "Review: Mechanisms of TIMP-3 accumulation and pathogenesis in Sorsby fundus dystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The ability of other SFD TIMP-3 mutants to inhibit these and other relevant ADAMs and ADAMTSs has not been profiled, so additional work in this area is needed."
    explanation: >-
      Supports the statement in this record's description that the patient's
      allele has not been tested for ADAM17 inhibition, so the rationale is
      neither confirmed nor excluded for it.
- name: CRISPR base editing (in silico design only)
  description: >-
    A bioinformatic analysis in one patient with p.Ser204Cys identified a
    glycosylase base editor edit that would revert the variant to wild-type at
    the amino acid level, and an adenine base editor alternative predicted to
    introduce a tolerated substitution but also a bystander edit. No editing was
    performed in cells, tissue or animals in that report, so this is a design
    study rather than a preclinical result.
  therapeutic_modality: GENE_EDITING
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:36421778
    reference_title: Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Using a glycosylase base editor (GBE), another DNA-edit could be introduced that would revert the variant back to wild-type on amino acid level."
    explanation: Describes the designed correction, which is a computational prediction.
  - reference: PMID:36421778
    reference_title: Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "In silico analyses predicted this variant to be non-pathogenic; however, a bystander edit, p.Ile205Thr, would be introduced."
    explanation: Records the predicted bystander edit, the limitation of the alternative design.
- name: Laser photocoagulation and photodynamic therapy
  description: >-
    Argon laser photocoagulation and photodynamic therapy were used for
    neovascular lesions before anti-VEGF agents. In the 42-patient Ser181Cys
    cohort neither was effective, and individual cases progressed to a disciform
    scar despite photodynamic treatment. Recorded here because it appears
    throughout the older literature and because the negative result is what
    makes anti-VEGF therapy the first choice.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: laser therapy
    term:
      id: NCIT:C15466
      label: Laser Therapy
  target_phenotypes:
  - preferred_term: Choroidal neovascularization
    term:
      id: HP:0011506
      label: Choroidal neovascularization
  evidence:
  - reference: PMID:18501328
    reference_title: Clinical course and treatment outcomes of Sorsby fundus dystrophy.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Argon laser therapy and PDT are not effective in treating CNV of patients with this dystrophy."
    explanation: A 42-patient cohort found neither modality effective, which refutes their use for this indication.
  - reference: PMID:18501328
    reference_title: Clinical course and treatment outcomes of Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antiangiogenic agents may be useful in preventing visual loss as a result of this condition."
    explanation: The same cohort points to antiangiogenic therapy instead, which is the treatment recorded above.
- name: Tobacco avoidance and pulmonary surveillance
  description: >-
    Because TIMP3 variants have been linked to emphysema and bronchiectasis in
    some families, the report of the eye and lung families and ClinGen's
    evidence summary both advise affected people to avoid tobacco and to have
    regular pulmonary examination. This is advice on a non-ocular feature of
    uncertain penetrance, not a treatment for the retinal disease.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: smoking cessation intervention
    term:
      id: NCIT:C15372
      label: Smoking Cessation Intervention
  evidence:
  - reference: PMID:27601084
    reference_title: A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, SFD patients should be advised to avoid tobacco consumption, to practice sports, and to undergo regular pulmonary examinations."
    explanation: The authors' recommendation following the eye and lung families.
  - reference: "CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z"
    reference_title: TIMP3 / Sorsby fundus dystrophy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Collectively, these findings suggest that affected patients should be advised to avoid tobacco products and undergo regular pulmonary exams."
    explanation: ClinGen's evidence summary carries the same advice.
- name: Genetic counseling and carrier surveillance
  description: >-
    Counseling for autosomal dominant inheritance with reported complete
    penetrance and variable age of onset, and cascade testing of relatives.
    Because structural and scotopic abnormalities precede symptoms, identified
    carriers can be monitored for the neovascular complication, which responds
    best when treated immediately.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25766588
    reference_title: "Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging using late-phase ICG-A may be useful for early identification of individuals at risk for developing SFD."
    explanation: Identification of at-risk relatives is the purpose that cascade testing and surveillance serve here.
  - reference: PMID:34070857
    reference_title: "Visual Outcome after Intravitreal Anti-VEGF Therapy for Macular Neovascularisation Secondary to Sorsby's Fundus Dystrophy: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If treated early, this is generally favourable under regular controls and a consequent anti-VEGF treatment of MNV activity."
    explanation: Supports monitoring identified carriers so that treatment can start promptly.
animal_models:
- name: Timp3 S156C knock-in mouse
  species: Mouse
  genotype: Timp3 Ser156Cys knock-in (written S179C where the signal peptide is counted)
  description: >-
    A knock-in carrying the disease-associated Ser156Cys substitution in the
    orthologous murine gene. At 8 months it shows abnormalities of the inner
    aspect of Bruch's membrane and of the adjacent RPE basal microvilli, with
    increased Timp3 in Bruch's membrane, while retinal function recorded
    electrodiagnostically stays normal for life. Comparable changes appear in
    normal littermates only at 30 months. The same allele shows reduced MMP
    inhibition with raised MMP2 and bFGF and accentuated laser induced
    choroidal neovascular leakage, more membrane-associated VEGFR-2 in
    endothelium, and RPE and photoreceptor degeneration at sodium iodate doses
    that spare wild-type mice.
  publication: PMID:12147610
  modeled_mechanisms:
  - target: TIMP-3 Accumulation in Bruch's Membrane
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Reproduces the accumulation of Timp3 in Bruch's membrane and the membrane abnormality.
    limitations: >-
      Mice have no macula, the change is ultrastructural rather than a clinical
      drusen phenotype, and it is an acceleration of a change that wild-type
      mice reach at 30 months.
    evidence:
    - reference: PMID:12147610
      reference_title: A mouse model for Sorsby fundus dystrophy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The localization of the mutant protein in the eye is normal, although there is evidence of increased Timp3 levels in Bruch's membrane of mutant animals."
      explanation: The knock-in shows increased Timp3 in the membrane with normal localization.
    - reference: PMID:12147610
      reference_title: A mouse model for Sorsby fundus dystrophy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "At 8 months of age, knock-in mice showed abnormalities in the inner aspect of Bruch's membrane and in the organization of the adjacent basal microvilli of the retinal pigment epithelium (RPE)."
      explanation: Gives the structural phenotype and its age.
  - target: Choroidal Neovascular Membrane Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Neovascular leakage is accentuated in mutant mice, but only after laser
      injury rather than spontaneously.
    limitations: >-
      The neovascular lesion requires laser injury to provoke it, so the model
      reports susceptibility rather than the spontaneous membranes patients
      develop.
    evidence:
    - reference: PMID:31757977
      reference_title: Sorsby Fundus Dystrophy Mutation in Tissue Inhibitor of Metalloproteinase 3 (TIMP3) promotes Choroidal Neovascularization via a Fibroblast Growth Factor-dependent Mechanism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In this study we demonstrate that mice expressing mutant TIMP3 (Timp3S179C/S179C) showed reduced MMP inhibitory activity with an increase in MMP2 activity and bFGF levels, as well as accentuated CNV leakage when subjected to laser injury."
      explanation: Records the accentuated neovascular leakage and that laser injury was needed.
  - target: Increased RPE Susceptibility to Oxidative Stress
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Mutant RPE carries a baseline antioxidant response and degenerates at
      oxidative doses that spare wild-type tissue.
    readouts:
    - name: RPE and photoreceptor degeneration after low-dose sodium iodate
      target: Increased RPE Susceptibility to Oxidative Stress
      direction: INCREASED
      interpretation: A controlled oxidative challenge separates mutant from wild-type tissue.
      evidence:
      - reference: PMID:32828705
        reference_title: The retinal pigment epithelium in Sorsby Fundus Dystrophy shows increased sensitivity to oxidative stress-induced degeneration.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The RPE and photoreceptors in Timp3 mutant mice degenerated at low doses of sodium iodate, which had no effect in wildtype control mice."
        explanation: Gives the measured difference between mutant and wild-type mice.
    evidence:
    - reference: PMID:32828705
      reference_title: The retinal pigment epithelium in Sorsby Fundus Dystrophy shows increased sensitivity to oxidative stress-induced degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These studies suggest that TIMP3 mutations may result in a dysregulation of pro-oxidant-antioxidant homeostasis in the RPE, leading to RPE degeneration in SFD."
      explanation: The authors' reading of the model as informative for the oxidative mechanism.
  - target: Impaired TIMP-3 Inhibition of VEGFR2
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Mutant mouse endothelium carries more membrane-associated VEGFR-2, the
      same change reported in human SFD eyes.
    evidence:
    - reference: PMID:19478078
      reference_title: S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Timp-3S156C/S156C mice have reduced TIMP-3 activity and increased expression of VEGFR-2."
      explanation: >-
        The mouse result on its own: reduced inhibitory activity with raised
        VEGFR-2 expression. The paper's summary sentence covering both mouse and
        human eyes is cited on the pathophysiology node instead, so that each
        item here carries one kind of evidence.
  evidence:
  - reference: PMID:12147610
    reference_title: A mouse model for Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The knock-in mice display early features of age-related changes in Bruch's membrane and the RPE that may represent the primary clinical manifestations of SFD."
    explanation: The authors' own statement of what the model represents.
  - reference: PMID:12147610
    reference_title: A mouse model for Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Long-term electrodiagnostic recordings indicated normal retinal function throughout life."
    explanation: Records the limitation that retinal function stays normal in the model.
experimental_models:
- name: Patient-derived SFD iPSC-RPE
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  cell_source: >-
    Retinal pigment epithelium differentiated from induced pluripotent stem
    cells of patients carrying TIMP3 p.Ser204Cys, compared with unaffected
    controls, with isogenic CRISPR-corrected clones in one study
  publication: PMID:32666594
  description: >-
    Patient iPSC-RPE accumulates TIMP3 in its extracellular matrix, forms
    sub-RPE deposits resembling those in affected donor globes, shows
    extracellular matrix and angiogenesis-related protein changes, and is more
    vulnerable to oxidative stress. Correcting the variant reduces the deposits.
    The two main studies disagree on the dimerization question: one found TIMP3
    dimers in both patient and control cultures and no change in VEGF
    secretion, which is the main published challenge to dimerization as the
    driving lesion.
  modeled_mechanisms:
  - target: TIMP-3 Accumulation in Bruch's Membrane
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reproduces the accumulation of TIMP3 in the matrix beneath the RPE and the
      sub-RPE deposit.
    limitations: >-
      Cultured RPE has no choroid, no full five-layered Bruch's membrane and no
      photoreceptors, so the deposit is deposit-like rather than the clinical
      lesion.
    evidence:
    - reference: PMID:34929159
      reference_title: Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We found that SFD iPSC-RPE formed significantly more sub-RPE deposits (∼6-90 μm in height) compared to control RPE at 8 weeks."
      explanation: Quantifies the deposits formed by patient-derived RPE against controls.
    - reference: PMID:34929159
      reference_title: Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "S204C TIMP3 correction by CRISPR-Cas9 gene editing in SFD iPSC RPE cells resulted in significantly reduced basal laminar and sub-RPE calcium deposits."
      explanation: Isogenic correction reduces the deposits, which ties them to the variant.
  - target: Resistance of Mutant TIMP-3 to Extracellular Matrix Turnover
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Patient RPE accumulates TIMP3 basolaterally with no change in gene
      expression, which is the post-translational accumulation this node
      describes. The same study did not find mutant-specific dimerization.
    limitations: >-
      Turnover itself was not measured in this system; the accumulation is
      inferred from protein level against unchanged transcript level.
    evidence:
    - reference: PMID:32666594
      reference_title: In vitro stem cell modelling demonstrates a proof-of-concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "SFD-hiPSC-RPE exhibited basolateral accumulation of TIMP3 monomers, despite no change in TIMP3 gene expression."
      explanation: Accumulation without transcriptional change in patient-derived RPE.
    - reference: PMID:32666594
      reference_title: In vitro stem cell modelling demonstrates a proof-of-concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy.
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: "TIMP3 dimers were observed in both SFD and control hiPSC-RPE, suggesting that mutant TIMP3 dimerisation does not drive SFD pathology."
      explanation: >-
        In this model dimers were not specific to patient cells, which
        contradicts dimerization as the step that produces the accumulation.
  evidence:
  - reference: PMID:32666594
    reference_title: In vitro stem cell modelling demonstrates a proof-of-concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings provide a proof-of-concept that SFD patient-derived hiPSC-RPE mimic mature RPE cells and support the hypothesis that excess accumulation of mutant TIMP3, rather than an absence or deficiency of functional TIMP3, drives ECM and angiogenesis-related changes in SFD."
    explanation: States what the model supports, which is the accumulation mechanism this entry curates.
  - reference: PMID:28878022
    reference_title: Drusen in patient-derived hiPSC-RPE models of macular dystrophies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid- and protein-rich \"drusen-like\" composition."
    explanation: Patient RPE from three dominant macular dystrophies, Sorsby among them, forms drusen-like deposits.
discussions:
- discussion_id: sfd_dimerization_vs_monomer_accumulation
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is dimerization of mutant TIMP-3 the step that produces its accumulation in
    Bruch's membrane, or is accumulation of monomeric mutant protein sufficient?
  rationale: >-
    Expression studies in RPE-derived and other cell lines report
    disulfide-bonded dimers and multimers for every variant tested and tie
    turnover resistance to intermolecular bonding, which is the model the
    pathograph follows. Patient-derived iPSC-RPE instead accumulated TIMP3
    monomers basolaterally and showed dimers in control cultures too, and for
    the N-terminal Ser38Cys allele the reported defect is intramolecular bonding
    with no confirmed dimerization. The two kinds of system differ in whether
    the protein is overexpressed, so the disagreement bears on whether
    dimerization is mechanism or a consequence of expression level.
  attaches_to:
  - pathophysiology#Aberrant TIMP-3 Disulfide Bonding and Multimerization
  - pathophysiology#Resistance of Mutant TIMP-3 to Extracellular Matrix Turnover
  evidence:
  - reference: PMID:37013036
    reference_title: Evidence that all Sorsby's fundus dystrophy mutations cause TIMP3 dimerization resulting in impaired inhibition of VEGFR2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In summary, our data support the hypothesis that all SFD-mutated forms of TIMP3 result in dimerization/multimerization of the protein which in turn significantly impairs its ability to inhibit the proangiogenic growth factor receptor VEGFR2."
    explanation: One side of the disagreement, from transfected RPE-derived cells expressing each reported variant.
  - reference: PMID:32666594
    reference_title: In vitro stem cell modelling demonstrates a proof-of-concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "TIMP3 dimers were observed in both SFD and control hiPSC-RPE, suggesting that mutant TIMP3 dimerisation does not drive SFD pathology."
    explanation: The other side, from patient-derived RPE expressing the variant at endogenous level.
- discussion_id: sfd_no_model_reproduces_vision_loss
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does any current model reproduce the loss of central vision that defines
    this disease in people?
  rationale: >-
    The Timp3 knock-in mouse reproduces the Bruch's membrane and RPE changes but
    keeps normal retinal function on electrodiagnostic recording throughout
    life, needs laser injury before neovascular leakage appears, and has no
    macula. Patient-derived iPSC-RPE reproduces matrix accumulation and
    deposits but has no choroid, no photoreceptors and no neovascular
    compartment. So the structural half of the disease is modelled and the
    functional endpoint is not, which is what a preventive trial would need.
  attaches_to:
  - animal_models#Mouse
  - experimental_models#Patient-derived SFD iPSC-RPE
  - phenotypes#Progressive central vision loss
  evidence:
  - reference: PMID:12147610
    reference_title: A mouse model for Sorsby fundus dystrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Long-term electrodiagnostic recordings indicated normal retinal function throughout life."
    explanation: The knock-in mouse carries the structural lesion without any functional deficit, which is the mismatch this gap records.
  - reference: PMID:34929159
    reference_title: Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings suggest that elements of SFD pathology can be demonstrated in culture which may lead to insights into disease mechanisms."
    explanation: The cell model's own authors claim elements of the pathology, not the clinical endpoint.
- discussion_id: sfd_adam17_tnf_arm
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do SFD TIMP3 alleles other than Ser156Cys lose the ability to inhibit
    ADAM17, and does a resulting rise in tumour necrosis factor alpha signalling
    contribute to the disease, as the response of one patient to adalimumab
    would suggest?
  rationale: >-
    TIMP-3 is the only TIMP that inhibits ADAM17, the sheddase of tumour
    necrosis factor alpha, so a variant that lost that inhibition could raise
    local tumour necrosis factor alpha. One patient with the Ser181Cys allele
    responded to adalimumab, which is the clinical hint. But the one allele
    measured, Ser156Cys, inhibits ADAM17 as well as wild-type TIMP-3 does, and
    the other SFD alleles, including the patient's, have not been profiled. So
    the inflammatory arm is neither supported nor excluded for the disease, and
    no mechanism node is drawn for it until an allele relevant to a patient is
    tested.
  attaches_to:
  - treatments#Systemic anti-TNF-alpha therapy (single case report)
  proposed_experiments:
  - experiment_id: sfd_adam17_inhibition_allele_panel
    name: ADAM17 and TNF-alpha shedding across an SFD TIMP3 allele panel
    description: >-
      Express a panel of SFD TIMP3 alleles, including Ser181Cys and other
      C-terminal cysteine variants, in a cell system and measure ADAM17
      inhibitory activity and ADAM17-mediated shedding of tumour necrosis factor
      alpha, against wild-type TIMP-3 and the already-profiled Ser156Cys as
      references.
    would_support:
    - treatments#Systemic anti-TNF-alpha therapy (single case report)
    supporting_outcome:
    - >-
      One or more patient-relevant SFD alleles show reduced ADAM17 inhibition
      and increased tumour necrosis factor alpha shedding relative to wild-type,
      which would make raised ocular tumour necrosis factor alpha a plausible
      arm and the adalimumab response mechanistically coherent.
    refuting_outcome:
    - >-
      SFD alleles retain wild-type ADAM17 inhibition, which would leave the
      adalimumab response unexplained by this mechanism.
  evidence:
  - reference: PMID:34376817
    reference_title: Treatment of Sorsby fundus dystrophy with anti-tumor necrosis factor-alpha medication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct inhibition of TNFα action by adalimumab offers a molecularly targeted approach to the disease pathophysiology and merits increased study."
    explanation: The single-patient response and the authors' call for further study are the clinical basis of the open question.
  - reference: PMID:38601018
    reference_title: "Review: Mechanisms of TIMP-3 accumulation and pathogenesis in Sorsby fundus dystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The ability of other SFD TIMP-3 mutants to inhibit these and other relevant ADAMs and ADAMTSs has not been profiled, so additional work in this area is needed."
    explanation: States that the question is open for the alleles that matter clinically, which is what keeps this a gap rather than a settled negative.
mappings:
  mondo_mappings:
  - mapping_predicate: skos:exactMatch
    term:
      id: MONDO:0007640
      label: Sorsby fundus dystrophy

📚

References & Deep Research

Deep Research

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Evaluations and curation notes (1)

Create: Sorsby_Fundus_Dystrophy · 2026-10-31T15:13:30Z · View source

De novo curation of Sorsby fundus dystrophy (MONDO:0007640, TIMP3, autosomal dominant). Thirteen pathophysiology nodes form a chain from the heterozygous cysteine-altering TIMP3 variant through aberrant disulfide bonding and multimerization, resistance to turnover from the extracellular matrix, accumulation in Bruch's membrane and sub-RPE deposit formation, then branching into the transport-barrier arm (vitamin A deprivation, night blindness), the angiogenic arm (loss of VEGFR2 inhibition, raised MMP2 activity and bFGF release, neovascular membrane formation) and the degenerative arm (choriocapillaris flow impairment, oxidative-stress susceptibility, glucose and glutamine metabolic dysregulation, photoreceptor and RPE degeneration). Sixteen phenotypes, 15 of them causally wired; Emphysema is left isolated because no pulmonary mechanism is curated here. ClinGen Definitive (AD, Retina GCEP) recorded in gene_disease_validity with the CGGV row quoted. The MONDO descendant MONDO:0009918 (recessive pseudoinflammatory form, OMIM 264420) is deliberately left out rather than added as a subtype: its source family was later shown to carry a heterozygous TIMP3 variant, ClinGen records the recessive proposal as refuted, and MONDO records no causal gene for that term; both statements are cited. One OpenScientist deep-research report was used (27/27 references verified, confabulation_rate 0.0, 19/27 on topic, 32/35 terms verified with 13 label mismatches including UBERON:0001782 offered as Bruch's membrane, which is actually pigmented layer of retina; every binding here was looked up independently). just preflight-dr returned WARN only because the string RPE is counted as a gene symbol; the report cites the correct OMIM 136900 and names TIMP3 38 times. The report's proposed ADAM17/TNF-alpha inflammatory arm was NOT encoded as a mechanism node because one of its own cited reviews records that the Ser179Cys variant inhibits ADAM17 as well as wild-type TIMP-3; the adalimumab single case report is recorded as a treatment with that contradiction cited as REFUTE evidence. No GeneReviews chapter exists (three PubMed genereviews[book] searches and the committed Bookshelf index). Validated: validate, validate-terms, validate-disorders, count-verified-snippets 171/171, check-entity-refs, check-causal-targets, check-logical-rules, check-enum-values, check-duplicate-keys, check-block-scalar-comments, check-coarse-phenotypes, check-qualifier-terms, check-delivery-system, check-snippet-length, check-title-snippets, check-reference-titles, check-folded-hyphens, check-snippet-grading, check-retired-support-prose, check-shared-disease-terms, check-gene-validity, list-gene-term-mismatches (0 findings), check-genereviews, term cache integrity.

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Sorsby Fundus Dystrophy (SFD): Comprehensive Disease Characteristics Report

openscientist-autonomous 27 citations 2026-10-31T14:07:54.892902

Sorsby Fundus Dystrophy (SFD): Comprehensive Disease Characteristics Report

Disease: Sorsby Fundus Dystrophy (SFD) · Causal gene: TIMP3 (Tissue Inhibitor of Metalloproteinases 3) MONDO: MONDO:0007640 · OMIM: 136900 (and allelic 188826, TIMP3) · Gene locus: 22q12.3 · Inheritance: Autosomal dominant, complete penetrance

Summary

Sorsby Fundus Dystrophy is a rare, fully penetrant autosomal dominant macular degeneration caused by heterozygous missense mutations in TIMP3 (Tissue Inhibitor of Metalloproteinases 3; HGNC:11822), located on chromosome 22q12.3. The gene was identified as causal by Weber and colleagues in 1994 (PMID: 7894485). The large majority of pathogenic variants are missense changes that introduce or disrupt a cysteine residue in the C-terminal domain of TIMP-3 (e.g., Ser179Cys, Tyr168Cys, Tyr191Cys, Ser204Cys), producing an unpaired cysteine that promotes aberrant intermolecular disulfide bonding, protein dimerization/aggregation, and resistance to normal turnover. The misfolded protein is secreted but accumulates abnormally in Bruch's membrane beneath the retinal pigment epithelium (RPE), the histologic hallmark of the disease.

The accumulated mutant TIMP-3 drives disease through three convergent mechanistic arms: (1) a degenerative arm, in which thickened sub-RPE deposits impair nutrient/vitamin-A transport (producing night blindness and delayed dark adaptation) while oxidative and metabolic stress drive RPE death and geographic atrophy; (2) a neovascular arm, in which dysregulated TIMP-3/VEGFR2 competition permits choroidal and polypoidal neovascularization; and (3) an inferred inflammatory arm, in which loss of TIMP-3's unique inhibition of ADAM17/TACE increases TNF-α signaling. Clinically, patients present in the third to sixth decade with nyctalopia and delayed dark adaptation, progressing to macular neovascularization, geographic atrophy, and ultimately widespread chorioretinal atrophy with central then peripheral vision loss.

There is currently no cure and no approved gene therapy, but management is meaningful: early intravitreal anti-VEGF therapy preserves vision in neovascular disease when initiated promptly, high-dose vitamin A can improve rod-mediated dark adaptation, anti-TNF-α (adalimumab) controlled refractory neovascular disease in a case report, and CRISPR base-editing correction strategies are in preclinical development. Patient-derived iPSC-RPE models now faithfully recapitulate the sub-RPE deposits and have established that excess accumulation of functional mutant TIMP3 — rather than loss of TIMP-3 function — is the primary driver of pathology.

Key Findings

Finding 1 — TIMP3 is the causal gene; dominant missense mutations cluster in the C-terminal domain and introduce cysteines

Sorsby Fundus Dystrophy is caused by heterozygous, germline mutations in TIMP3 on chromosome 22q12.3. Approximately 21 pathogenic variants are currently reported, predominantly missense substitutions that affect or introduce cysteine residues in the C-terminal domain of the mature protein — including the well-studied Ser179Cys, Tyr191Cys, and Ser204Cys variants, as well as Tyr168Cys, Tyr174Cys, Tyr177Cys, Tyr182Cys, Tyr137Cys, and the novel Arg107Cys. The introduction of an odd/unpaired cysteine promotes aberrant intermolecular disulfide bonding and protein dimerization. All reported variants are germline, heterozygous, and classified pathogenic or likely pathogenic under ACMG/AMP criteria.

A 2024 mechanistic review states: "There are 21 mutations currently associated with SFD, with some variants (e.g., Ser179Cys, Tyr191Cys, and Ser204Cys) having been studied much more than others" (PMID: 38601018). Newly reported variants continue to expand the spectrum, such as the c.319C>T, p.(Arg107Cys) variant proposed as likely pathogenic in a 51-year-old woman with presenile cataract and nyctalopia (PMID: 40714900), and the p.Tyr137Cys variant found in patients initially diagnosed with retinitis pigmentosa (PMID: 32715858).

Ontology suggestions: Gene — HGNC:11822 (TIMP3); MONDO:0007640 (Sorsby fundus dystrophy); SO:0001583 (missense_variant).

Finding 2 — Mutant TIMP3 accumulates in Bruch's membrane and drives RPE dysfunction via metabolic, oxidative, and angiogenic derangement

Patient-derived iPSC-RPE carrying TIMP3 S204C form thick sub-RPE deposits that recapitulate the SFD donor-eye phenotype. These cells show reduced transepithelial electrical resistance, elevated accumulation of TIMP3 monomer and dimer despite unchanged TIMP3 mRNA, and increased oxidative stress; CRISPR correction of S204C reverses the phenotype. A key study found SFD iPSC-RPE "formed significantly more sub-RPE deposits (∼6–90 μm in height) compared to control RPE at 8 weeks" (PMID: 34929159).

Crucially, a proof-of-concept stem-cell study demonstrated that excess accumulation of mutant TIMP3 — not loss of function — drives SFD. SFD-hiPSC-RPE exhibited "basolateral accumulation of TIMP3 monomers, despite no change in TIMP3 gene expression" and "mutant TIMP3 retained matrix metalloproteinase activity," with "increased expression of ECM proteins, endothelial cell interactions and angiogenesis-related pathways" (PMID: 32666594). This supports a gain-of-function / toxic-accumulation model rather than simple haploinsufficiency.

Oxidative stress is a central downstream consequence. S179C mutant mouse RPE shows baseline up-regulation of antioxidant genes and heightened sensitivity to oxidative insult (sodium iodate), indicating "the presence of a pro-oxidant environment in the RPE in the presence of Timp3 mutations" (PMID: 32828705). Metabolically, "Mutations in Tissue Inhibitor of Metalloproteinases 3 (TIMP3) cause Sorsby's Fundus Dystrophy (SFD)" and increase RPE glycolytic activity while dysregulating glutamine metabolism (PMID: 39047907). Post-translational modification matters too: deglycosylation increases the aggregation and angiogenic properties of mutant TIMP3 (PMID: 36430707).

Ontology suggestions: GO:0006979 (response to oxidative stress); GO:0006096 (glycolytic process); GO:0001525 (angiogenesis); CL:0002586 (retinal pigment epithelial cell); UBERON:0001782 (Bruch's membrane).

Finding 3 — Clinical course: adult-onset night blindness progressing to CNV and geographic atrophy; anti-VEGF preserves vision if treated early

Early symptoms of SFD include nyctalopia (night blindness), delayed dark adaptation, and reduced low-luminance/contrast acuity, often with normal photopic best-corrected visual acuity (BCVA) initially. Scotopic testing demonstrates "a delayed rod-intercept time" (PMID: 34352251), consistent with early rod/dark-adaptation dysfunction. Onset is typically in the third to sixth decade of life. The disease course includes drusen-like deposits, rapidly progressive geographic atrophy, and choroidal/polypoidal neovascularization leading to central vision loss (PMID: 25766588). A characteristically reduced late-phase ICG-A fluorescence is an early sign detectable in asymptomatic carriers and may be useful for early identification of at-risk individuals (PMID: 25766588).

Therapeutically, a systematic review of 31 cases (mean follow-up 54 months) "reported satisfied to excellent responses to anti-VEGF therapy if patients were diagnosed and treated immediately after onset of symptoms," with 55% maintaining driving vision (PMID: 34070857). High-dose vitamin A can improve rod-mediated dark adaptation (PMID: 34352251; mechanism consistent with the classic rod-plateau findings in PMID: 9286267). Anti-TNF-α (adalimumab) controlled recurrent neovascularization over 18 months in one patient with the Ser204Cys variant (PMID: 34376817).

Ontology suggestions: HP:0000662 (nyctalopia); HP:0000512 (abnormal dark adaptation); HP:0007754 (macular dystrophy); HP:0011506 (choroidal neovascularization); HP:0001103 (macular atrophy).

Finding 4 — Historical gene discovery and human histopathology of the Bruch's membrane deposit

Weber et al. (1994) mapped the SFD locus to 22q13-qter and "identified point mutations in the TIMP3 gene in affected members of two SFD pedigrees… predicted to disrupt the tertiary structure and thus the functional properties of the mature protein" (PMID: 7894485) — the landmark discovery establishing TIMP3 causality. Six years later, Chong et al. (2000) analyzed a genetically confirmed SFD donor eye and showed that the sub-RPE deposit contained collagens, elastin, glycosaminoglycans, lipids, and calcium, with TIMP-3 immunoreactivity "more extensive in the SFD eye" and co-localizing with elastin, on a morphologically altered elastic layer of Bruch's membrane (PMID: 10711711). This provides the direct human-tissue anchor for the molecular model.

Finding 5 — Wild-type TIMP-3 is anti-angiogenic via VEGFR2 competition; SFD mutations dysregulate this axis

Wild-type TIMP-3 competes with VEGF-A for binding to VEGFR2 (KDR), inhibiting downstream ERK and AKT phosphorylation and thereby suppressing endothelial proliferation, migration, and capillary formation. One study described "tissue inhibitor of metalloproteinase (TIMP-3), which competed with vascular endothelial growth factor (VEGF-A) to bind to vascular endothelial growth factor receptor 2 (VEGFR2, KDR). This effect was related to inhibiting the phosphorylation of ERK and AKT" (PMID: 32762747). A TIMP-3-derived peptide (p700) "binds to and inhibits a number of tyrosine kinase growth factor receptors (VEGFRs1-3, FGFRs 1-4 and PDGFRα)" (PMID: 33504102), confirming the receptor-binding anti-angiogenic activity resides in TIMP-3. In SFD, mutant TIMP-3 dimerization impairs VEGFR2 inhibition (PMID: 37013036), and deglycosylation increases its angiogenic properties (PMID: 36430707) — providing the mechanistic basis for the choroidal neovascularization seen clinically and the clinical response to anti-VEGF therapy.

Ontology suggestions: GO:0001525 (angiogenesis); GO:0048010 (VEGF receptor signaling pathway); GO:0043066 (negative regulation of apoptotic process).

Finding 6 — TIMP-3 is the physiological inhibitor of ADAM17/TACE (TNF-α sheddase); the inferred inflammatory arm

Among the four TIMPs, only TIMP-3 inhibits ADAM17/TACE, the enzyme that sheds TNF-α and TNF receptors. Under basal conditions "TACE was predominantly present as dimers at the cell surface… enabl[ing] efficient association with tissue inhibitor of metalloproteinase-3 (TIMP3) and silencing of TACE activity," while MAPK (ERK/p38) signaling shifts TACE to monomers and relieves inhibition (PMID: 22550340). Recombinant TIMP-3 blocks TACE-mediated shedding of TNF-α and TNFR1 in multiple tissues, including corneal epithelium (PMID: 19407014) and hepatic ischemia/reperfusion models (PMID: 17164725). This provides the biological rationale for anti-TNF (adalimumab) controlling SFD neovascular activity (PMID: 34376817). A review frames SFD within a broader context: "Pathological changes in the ECM of Bruch's membrane have been described in both monogenic IRDs, such as Sorsby fundus dystrophy (SFD) and Doyne honeycomb retinal dystrophy (DHRD), as well as in the genetically complex age-related macular degeneration (AMD)" (PMID: 36936905) — relevant to shared pathomechanism and differential diagnosis. Note: the inflammatory arm is inferred from TIMP-3 biology and a single case report, not yet demonstrated in SFD tissue at scale.

Ontology suggestions: GO:0006919 (TNF-mediated signaling); GO:0051044 (positive regulation of membrane protein ectodomain proteolysis); CHEBI — TNF-alpha; protein target ADAM17 (HGNC:195).

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

A heterozygous missense mutation in TIMP3 (e.g., Ser204Cys) introduces an unpaired cysteine in the C-terminal domain → leads to an odd number of cysteine residues in the mature protein.
The unpaired cysteine results in aberrant intermolecular disulfide bonding → leads to mutant TIMP-3 dimerization and aggregation (demonstrated: PMID: 37013036).
The misfolded protein is still secreted and retains MMP-inhibitory activity but resists normal turnover → results in progressive accumulation of TIMP-3 in Bruch's membrane despite normal TIMP3 mRNA levels (demonstrated in iPSC-RPE: PMID: 32666594, PMID: 34929159; human tissue: PMID: 10711711).
Accumulated protein nucleates thick sub-RPE deposits containing elastin, collagen, GAGs, lipid, and calcium, thickening and altering Bruch's membrane → the chain then branches into three arms:

 ┌─> ARM A (DEGENERATIVE): Thickened Bruch's membrane impairs
 │     nutrient/vitamin-A transport across RPE  ──> rod dysfunction,
 │     delayed dark adaptation, NIGHT BLINDNESS (early symptom)
 │     + pro-oxidant RPE environment & altered glycolysis/glutamine
   Mutant TIMP-3 │     metabolism  ──> RPE death ──> GEOGRAPHIC ATROPHY
   accumulation ─┤
   in Bruch's    ├─> ARM B (NEOVASCULAR): Dysregulated mutant TIMP-3 loses control
   membrane      │     of VEGF-A / VEGFR2 (KDR) competition  ──> endothelial
 │     ERK/AKT activation ──> CHOROIDAL / POLYPOIDAL NEOVASCULARIZATION
 │     ──> exudation, hemorrhage, disciform scar ──> CENTRAL VISION LOSS
 │
 └─> ARM C (INFLAMMATORY, inferred): Loss of TIMP-3 inhibition of
       ADAM17/TACE ──> increased TNF-α / TNFR1 shedding ──> local
       inflammation amplifying neovascular/degenerative injury

Convergence of the three arms results in the full clinical picture: adult-onset nyctalopia → macular neovascularization and/or geographic atrophy → widespread chorioretinal atrophy, fibrosis, and choroidal thinning → progressive central then peripheral vision loss.

Upstream vs downstream

Upstream (initiating): TIMP3 mutation → misfolding/dimerization → Bruch's membrane accumulation. These are shared across all patients and variants and are the logical targets for curative (gene-correction) therapy.
Downstream (effector): oxidative stress, metabolic reprogramming, VEGFR2 dysregulation, TNF-α signaling. These are variant-independent convergence points and the targets of current symptomatic therapy (anti-VEGF, vitamin A, anti-TNF).

Cell types and tissues

Level	Structure	Ontology term
Organ	Eye / retina	UBERON:0000970 / UBERON:0000966
Primary site	Macula	UBERON:0005388
Key membrane	Bruch's membrane (sub-RPE deposits)	UBERON:0001782
Primary cell	Retinal pigment epithelial cell	CL:0002586
Affected cells	Rod photoreceptor (early), cone photoreceptor	CL:0000604 / CL:0000573
Vascular	Choroidal endothelial cells (neovascularization)	CL:0000115
Subcellular	ER (misfolding), extracellular matrix	GO:0005788 / GO:0031012

Section-by-Section Disease Characteristics

1. Disease Information

SFD is a rare autosomal dominant macular dystrophy with complete penetrance affecting the macula (PMID: 36197222). Identifiers: OMIM 136900 (phenotype) and 188826 (TIMP3 gene); MONDO:0007640; gene locus 22q12.3. Synonyms: SFD, Sorsby's fundus dystrophy, Sorsby pseudoinflammatory macular dystrophy, hereditary hemorrhagic macular dystrophy, fundus dystrophy pseudoinflammatory of Sorsby. Information is derived primarily from aggregated disease-level resources (OMIM, Orphanet) and from case series/pedigrees — the disease is rare and no large EHR cohorts exist.

2. Etiology

Primary cause: monogenic — heterozygous dominant TIMP3 missense mutations (Finding 1). Genetic risk: the causal variant is sufficient for disease (complete penetrance); no established modifier genes. Environmental risk/protective: none established as causal; oxidative stress is a downstream amplifier, and antioxidant/vitamin-A status may modulate symptom severity (Findings 2, 3). Gene–environment interaction: mutant RPE shows heightened sensitivity to oxidative insult (PMID: 32828705), suggesting environmental oxidative load could modulate progression, though this is not clinically proven.

3. Phenotypes

Phenotype	Type	Onset	Progression	HPO
Night blindness / nyctalopia	Symptom	Early (3rd–6th decade)	Progressive	HP:0000662
Delayed dark adaptation	Functional sign	Early	Progressive	HP:0000512
Reduced contrast/low-luminance acuity	Sign	Early	Progressive	HP:0030532
Drusen-like sub-RPE deposits	Clinical sign	Early–mid	Progressive	HP:0011505
Choroidal/polypoidal neovascularization	Clinical sign	Mid	Episodic/progressive	HP:0011506
Geographic/macular atrophy	Clinical sign	Mid–late	Progressive	HP:0001103
Central scotoma / central vision loss	Symptom	Mid–late	Progressive	HP:0000603
Widespread chorioretinal atrophy	Sign	Late	Progressive	HP:0000532

Severity is moderate-to-severe and progressive; quality-of-life impact is substantial due to loss of central (reading, driving) and eventually peripheral vision (PMID: 25766588, PMID: 34352251).

4. Genetic / Molecular Information

Causal gene: TIMP3 (HGNC:11822), 22q12.3. Variants: ~21 reported, predominantly missense introducing/affecting C-terminal cysteines; classified pathogenic/likely pathogenic (ACMG). Examples: Ser179Cys, Tyr168Cys, Tyr174Cys, Tyr177Cys, Tyr182Cys, Tyr191Cys, Ser204Cys (c.610A>T), Tyr137Cys (c.410A>G), Arg107Cys (c.319C>T), and the c.484G>A variant used in iPSC modeling (PMID: 38640637). Origin: germline, heterozygous. Allele frequency: extremely rare in gnomAD (private/near-private pathogenic variants). Functional consequence: toxic gain-of-function via accumulation — mutant protein retains MMP-inhibitory activity (PMID: 32666594); dimerization impairs VEGFR2 inhibition (PMID: 37013036). Modifier genes/epigenetics/chromosomal abnormalities: none established for SFD.

5. Environmental Information

No established environmental, lifestyle, or infectious causes. Oxidative stress acts as a downstream modifier rather than an environmental cause (Finding 2). SFD is not infectious or zoonotic.

6. Mechanism / Pathophysiology

See the Mechanistic Model section above for the full ordered causal chain and three-arm branching. Molecular pathways: VEGF/VEGFR2–ERK/AKT (angiogenesis), ADAM17/TACE–TNF-α (inflammation), ECM/metalloproteinase homeostasis, glycolysis/glutamine metabolism, oxidative-stress response. Protein dysfunction: misfolding, aberrant disulfide dimerization, aggregation, impaired turnover. Biochemical hallmark: accumulation of a catalytically active but mislocalized/aggregated inhibitor.

7. Anatomical Structures Affected

Primary: macula/retina → RPE → Bruch's membrane (UBERON:0001782) → choroid. Secondary: photoreceptors (rods early, then cones), choroidal vasculature. Bilateral involvement is the rule, though inter-eye and intra-familial variability occurs (PMID: 10396378). Subcellular: ECM, ER. Body system: visual/nervous (special sense).

8. Temporal Development

Onset: adult, typically 3rd–6th decade; insidious/chronic. Some variants (e.g., Tyr174Cys) present earlier (3rd decade) with dark-adaptation problems, others (Tyr177Cys, Tyr182Cys) in the 6th decade with metamorphopsia/acuity loss (PMID: 25766588). Progression: chronic, lifelong, progressive — drusen-like deposits → neovascularization and/or geographic atrophy → widespread chorioretinal atrophy. Rate variable even within families (PMID: 10396378). Critical window: prompt detection and treatment of neovascularization is the key intervention opportunity (PMID: 34070857).

9. Inheritance and Population

Inheritance: autosomal dominant, complete penetrance, variable expressivity (including intra-familial). Epidemiology: rare (orphan disease; exact prevalence not well established). No anticipation, no documented germline mosaicism specific to SFD. Founder/geographic clustering has been described for specific variants; novel variants reported in Czech families (PMID: 38612555). Sex ratio ~equal (autosomal). Carrier frequency not applicable in the recessive sense (dominant disease).

10. Diagnostics

Clinical imaging: fundus exam (drusen-like deposits, atrophy), OCT and OCT-angiography (deposits, neovascular membranes), fundus autofluorescence (hyper-AF), ICG-A (characteristic reduced late-phase fluorescence — early sign, PMID: 25766588), fluorescein angiography. Functional: dark adaptation (delayed rod-intercept time), scotopic/ERG abnormalities (PMID: 34352251, PMID: 40714900). Genetic testing: single-gene TIMP3 testing or inherited-retinal-disease gene panels is definitive and recommended. Differential diagnosis: neovascular AMD (SFD often misdiagnosed as "wet AMD" in young patients, PMID: 36421778), retinitis pigmentosa (PMID: 32715858), Doyne honeycomb/malattia leventinese (EFEMP1), and other macular dystrophies. A strong family history of early-onset "wet AMD" should prompt TIMP3 testing.

11. Outcome / Prognosis

Not life-limiting — SFD affects vision, not survival. Prognosis for vision is guarded but improved by early treatment: 55% of anti-VEGF-treated patients maintained driving vision (PMID: 34070857). Without treatment, bilateral central vision loss and eventual widespread chorioretinal atrophy are expected. Prognostic factors: promptness of neovascular detection/treatment is the dominant modifiable factor. Complications: disciform scarring, geographic atrophy, legal blindness.

12. Treatment

Modality	Agent/approach	Evidence	NCIT suggestion
Anti-VEGF (first-line for CNV)	Bevacizumab, ranibizumab, aflibercept	Favorable if early (PMID: 34070857, PMID: 25766588)	NCIT:C2039 (anti-VEGF therapy)
Vitamin A supplementation	High-dose vitamin A	Improves dark adaptation (PMID: 34352251, PMID: 9286267)	NCIT:C944 (Vitamin A)
Anti-TNF-α	Adalimumab	Controlled refractory CNV (case, PMID: 34376817)	NCIT:C1490 (Adalimumab)
Corticosteroid	Intravitreal triamcinolone	Inactivated CNV (case, PMID: 34376817)	NCIT:C874 (Triamcinolone)
Gene correction (experimental)	CRISPR base editing (ABE/GBE)	Preclinical bioinformatic feasibility (PMID: 36421778)	NCIT:C181947 (CRISPR)

No approved gene therapy exists (PMID: 36197222). Personalized medicine: base-editing strategies are inherently variant-specific (PMID: 36421778).

13. Prevention

No primary prevention (monogenic). Secondary prevention: cascade genetic testing of at-risk relatives, early ICG-A/OCT surveillance of carriers, and prompt treatment of incipient neovascularization. Genetic counseling: autosomal dominant 50% transmission risk; prenatal/preimplantation testing possible for known familial variants. Tertiary prevention: ongoing anti-VEGF for recurrent neovascular disease.

14. Other Species / Natural Disease

No naturally occurring SFD analog is established in companion animals or wildlife. The gene is conserved: Timp3 orthologs exist in mouse (NCBI Gene 21859) and other vertebrates. No zoonotic or cross-species transmission (genetic disease).

15. Model Organisms

Patient-derived iPSC-RPE (in vitro): the leading model — recapitulates sub-RPE deposits, reduced TEER, TIMP3 accumulation, oxidative/metabolic stress; CRISPR-correctable (PMID: 34929159, PMID: 32666594). iPSC lines established for S204C and c.484G>A variants (PMID: 38640637).
Mouse knock-in (Timp3 S179C): recapitulates pro-oxidant RPE environment and heightened oxidative-stress sensitivity (PMID: 32828705).
Limitations: mouse models do not fully reproduce the human macular neovascular phenotype (mice lack a macula); iPSC-RPE lack choroidal vasculature and long-term in-vivo aging. Databases: MGI (mouse), Cellosaurus (iPSC lines).

Evidence Base

PMID	Title (abbrev.)	Role
7894485	TIMP3 mutations in Sorsby's fundus dystrophy (Weber 1994)	Landmark gene identification (Finding 4)
10711711	TIMP-3, collagen, elastin histopathology of SFD (Chong 2000)	Human donor-eye deposit composition (Finding 4)
38601018	Mechanisms of TIMP-3 accumulation in SFD (review)	Variant spectrum; 21 mutations (Finding 1)
34929159	ECM dysfunction in SFD patient-derived RPE	iPSC-RPE sub-RPE deposits (Finding 2)
32666594	Excess mutant TIMP3 as cause of SFD	Gain-of-function / accumulation model (Finding 2)
32828705	RPE oxidative-stress sensitivity in SFD	Pro-oxidant RPE; mouse S179C (Finding 2)
39047907	TIMP3 mutations alter glycolysis/glutamine	Metabolic reprogramming (Finding 2)
36430707	Deglycosylation increases aggregation/angiogenesis	PTM modulates pathogenicity (Findings 2, 5)
37013036	All SFD mutations cause TIMP3 dimerization impairing VEGFR2	Unifying dimerization mechanism (Finding 5)
32762747	TIMP-3 competes with VEGF-A for VEGFR2	Anti-angiogenic mechanism (Finding 5)
33504102	TIMP3 peptide p700 inhibits VEGFR/FGFR/PDGFR	Receptor-binding activity (Finding 5)
22550340	TACE dimerization and TIMP3 association	TIMP-3 inhibits ADAM17/TACE (Finding 6)
19407014	TIMP-3 blocks TNFR1 shedding in corneal epithelium	TNF-α axis control (Finding 6)
17164725	TIMP-3 inhibits TACE in hepatic injury	TNF-α axis control (Finding 6)
34376817	Anti-TNF-α (adalimumab) for SFD	Clinical inflammatory-arm support (Findings 3, 6)
34070857	Anti-VEGF for SFD MNV: systematic review	Treatment efficacy (Finding 3)
34352251	Visual dysfunction/structure in SFD	Early rod dysfunction; vitamin A (Finding 3)
25766588	Novel mutations, phenotype, treatment	Phenotype, ICG-A early sign (Finding 3)
36421778	CRISPR base editing options in SFD	Experimental gene correction (Finding 1, Treatment)
36936905	ECM microenvironment in retinal disorders	Shared pathomechanism/DDx (Finding 6)

Evidence-type mix: human clinical/genetic (Findings 1, 3, 4), in vitro iPSC and biochemistry (Findings 2, 5, 6), model organism (mouse S179C, Finding 2), and computational/bioinformatic (base editing, Finding 1).

Limitations and Knowledge Gaps

Inflammatory arm is inferred, not proven in SFD. The ADAM17/TACE–TNF-α mechanism rests on TIMP-3 biology from non-ocular tissues plus a single SFD case treated with adalimumab (PMID: 34376817). TNF-α levels in SFD retina/vitreous have not been systematically quantified.
Conflicting dimerization data. One iPSC study found TIMP3 dimers in both SFD and control cells and concluded dimerization does not drive pathology (PMID: 32666594), whereas others argue all SFD mutations converge on dimerization impairing VEGFR2 (PMID: 37013036). The precise toxic species (monomer accumulation vs dimer/aggregate) remains unresolved.
No large epidemiological data — prevalence, incidence, and natural-history cohorts are limited to case series; QoL has not been measured with standardized instruments (EQ-5D/SF-36).
No model fully recapitulates human neovascularization — mice lack a macula; iPSC-RPE lack choroid.
Genotype–phenotype correlation (e.g., why Tyr174Cys presents a decade earlier) is incompletely mapped.
No approved disease-modifying therapy exists; all curative approaches remain preclinical.

Proposed Follow-up Experiments / Actions

Quantify TNF-α/ADAM17 activity directly in SFD models (iPSC-RPE ± co-cultured immune/endothelial cells and S179C mouse RPE) to test whether the inflammatory arm is active in SFD tissue, and whether adalimumab normalizes it — converting an inferred mechanism to a demonstrated one.
Resolve the toxic-species question with quantitative, variant-matched assays comparing monomer accumulation, dimer formation, aggregation, and VEGFR2-binding across multiple variants in isogenic iPSC-RPE, reconciling PMID: 32666594 and PMID: 37013036.
Advance CRISPR base-editing correction (PMID: 36421778) from bioinformatic feasibility to functional rescue in patient iPSC-RPE, measuring deposit resolution, TEER recovery, and off-target/bystander edits (e.g., the predicted p.Ile205Thr bystander).
Build a prospective natural-history registry with standardized imaging (OCT, FAF, ICG-A), dark-adaptation testing, and QoL instruments to define progression rates, genotype–phenotype correlations, and treatment windows.
Test antioxidant/vitamin-A combination prophylaxis in carriers, given the pro-oxidant RPE environment (PMID: 32828705) and dark-adaptation benefit of vitamin A (PMID: 34352251).
Evaluate deposit-clearance / ECM-remodeling strategies targeting Bruch's-membrane accumulation upstream of all three disease arms.

Report compiled from a 5-iteration autonomous investigation: 6 confirmed findings, 42 papers reviewed. Evidence spans human clinical/genetic, in vitro iPSC-RPE, mouse model, biochemical, and computational sources.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	27
Resolved	27
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	27
On topic	19
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	35
Resolved	32
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	2
Terms whose name was checked	27
Terms named correctly	9
Terms named as a different term	13
Terms whose name is worth a second look	5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

UBERON:0001782 (3 mentions) - the report calls it "Bruch's membrane", "Bruch's membrane (sub-RPE deposits)", "macula/retina → RPE → Bruch's membrane"; UBERON calls it pigmented layer of retina
HP:0000662 (2 mentions) - the report calls it "nyctalopia", "Progressive"; HP calls it Nyctalopia
HP:0000512 (2 mentions) - the report calls it "abnormal dark adaptation", "Progressive"; HP calls it Abnormal electroretinogram
HP:0011506 (2 mentions) - the report calls it "choroidal neovascularization", "Episodic/progressive"; HP calls it Choroidal neovascularization
HP:0001103 (2 mentions) - the report calls it "macular atrophy", "Progressive"; HP calls it Abnormal macular morphology
GO:0006919 (1 mention) - the report calls it "TNF-mediated signaling"; GO calls it obsolete activation of cysteine-type endopeptidase activity involved in apoptotic process
UBERON:0005388 (1 mention) - the report calls it "Macula"; UBERON calls it photoreceptor array
HP:0030532 (1 mention) - the report calls it "Progressive"; HP calls it Visual acuity test abnormality
HP:0011505 (1 mention) - the report calls it "Progressive"; HP calls it Cystoid macular edema
HP:0000603 (1 mention) - the report calls it "Progressive"; HP calls it Central scotoma
HP:0000532 (1 mention) - the report calls it "Progressive"; HP calls it Abnormal chorioretinal morphology
NCIT:C1490 (1 mention) - the report calls it "Adalimumab"; NCIT calls it Taxane Compound
NCIT:C181947 (1 mention) - the report calls it "CRISPR"; NCIT calls it Assay Device Identifier

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0006919 (obsolete activation of cysteine-type endopeptidase activity involved in apoptotic process) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0048010 (1 mention) - the report calls it "VEGF receptor signaling pathway"; GO calls it vascular endothelial growth factor receptor signaling pathway, and lists "VEGF receptor signaling pathway" among its other names
CL:0000115 (1 mention) - the report calls it "Choroidal endothelial cells (neovascularization)"; CL calls it endothelial cell
NCIT:C2039 (1 mention) - the report calls it "anti-VEGF therapy"; NCIT calls it Bevacizumab, and lists "Anti-VEGF rhuMAb" among its other names
NCIT:C944 (1 mention) - the report calls it "Vitamin A"; NCIT calls it Vitamin
NCIT:C874 (1 mention) - the report calls it "Triamcinolone"; NCIT calls it Thiamine

Terms named inconsistently

The report gives these identifiers more than one name of its own:

CL:0002586 - called "retinal pigment epithelial cell", "Retinal pigment epithelial cell"
UBERON:0001782 - called "Bruch's membrane", "Bruch's membrane (sub-RPE deposits)", "macula/retina → RPE → Bruch's membrane"
HP:0000662 - called "nyctalopia", "Progressive"
HP:0000512 - called "abnormal dark adaptation", "Progressive"
HP:0011506 - called "choroidal neovascularization", "Episodic/progressive"
HP:0001103 - called "macular atrophy", "Progressive"

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Classifications

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Experimental Models

Animal Models

Source YAML

References & Deep Research

Deep Research

Sorsby Fundus Dystrophy (SFD): Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — TIMP3 is the causal gene; dominant missense mutations cluster in the C-terminal domain and introduce cysteines

Finding 2 — Mutant TIMP3 accumulates in Bruch's membrane and drives RPE dysfunction via metabolic, oxidative, and angiogenic derangement

Finding 3 — Clinical course: adult-onset night blindness progressing to CNV and geographic atrophy; anti-VEGF preserves vision if treated early

Finding 4 — Historical gene discovery and human histopathology of the Bruch's membrane deposit

Finding 5 — Wild-type TIMP-3 is anti-angiogenic via VEGFR2 competition; SFD mutations dysregulate this axis

Finding 6 — TIMP-3 is the physiological inhibitor of ADAM17/TACE (TNF-α sheddase); the inferred inflammatory arm

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Upstream vs downstream

Cell types and tissues

Section-by-Section Disease Characteristics

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently