🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

OPTN-related glaucoma segregates as an autosomal dominant trait in the multigeneration pedigrees in which the gene was discovered and in subsequently reported E50K families. Penetrance is age-dependent and incomplete at younger ages: in the Moorfields series seven E50K carriers aged 23-58 years had normal discs and fields at the time of study, so an unaffected examination in a young carrier does not exclude later disease.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:11834836 SUPPORT Human Clinical

"In a study of 54 families with autosomal dominantly inherited adult-onset POAG, we identified the causative gene on chromosome 10p14 and designated it OPTN (for "optineurin")."

The gene-discovery study established OPTN as the causative gene in autosomal dominantly inherited adult-onset POAG pedigrees.

PMID:16043855 SUPPORT Human Clinical

"In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma."

Documents age-dependent, incomplete penetrance among carriers in the two studied families, supporting the penetrance caveat in the description.

◈

Mechanistic Hypotheses

2

Autophagic-lysosomal flux block as the primary lesion

autophagy_block_model CANONICAL

Evidence balance 2 support

The dominant model: mutant optineurin blocks autophagic flux in retinal ganglion cells, undegraded cargo accumulates, and the cells die by apoptosis. Supported by concordant LC3-II/p62 accumulation in knock-in mice, in E50K-expressing retinal cells, and in isogenic human stem cell-derived retinal ganglion cells, and by rescue on pharmacological induction of autophagy.

Show evidence (2 references)

PMID:31238079 SUPPORT Human Clinical

"Mutations in OPTN and TBK1 cause a dysregulation of autophagy which may directly cause retinal ganglion cell damage and normal tension glaucoma."

States the autophagy-dysregulation model as the accepted explanation for OPTN-related normal-tension glaucoma.

PMID:39425218 SUPPORT In Vitro

"the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN(E50K) RGCs"

The rescue-on-induction result that upgrades this from an association to a causal model.

Rab8-dependent vesicle trafficking failure as a parallel lesion

vesicle_trafficking_model ALTERNATIVE

Evidence balance 1 support

An alternative or contributory model in which the disease-relevant consequence of E50K is loss of the optineurin-Rab8 interaction and the consequent failure of Golgi-to-membrane vesicle transport and receptor recycling, with autophagic changes secondary. Demonstrated biochemically and in transgenic mouse retina, but without an equivalent rescue experiment tying it to ganglion cell survival.

Show evidence (1 reference)

PMID:20388642 SUPPORT Model Organism

"At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane."

Graded PARTIAL: establishes the trafficking lesion this model rests on, but does not by itself show that trafficking failure rather than the accompanying autophagy defect causes ganglion cell death.

?

Discussions and Knowledge Gaps

3

Do the optineurin mouse models, which all rely on mutant overexpression or homozygosity, faithfully represent a heterozygous human missense disease that spares the outer retina?

HUMAN MODEL MISMATCH OPEN optn_mouse_overexpression_fidelity

Attached to

pathophysiology#Retinal Ganglion Cell Apoptosis pathophysiology#Progressive Glaucomatous Optic Neuropathy at Normal Intraocular Pressure

Human OPTN-related glaucoma is a heterozygous, ganglion-cell-selective optic neuropathy. None of the three mouse models matches that genotype-phenotype pairing. The original transgenic line overexpresses mutant optineurin globally and degenerates panretinally, losing photoreceptors and non-RGC cells - features explicitly noted as not observed in human POAG. The BAC line was built to fix that, and does express near-physiologically, but its phenotype is an enhancement of an age-related decline detectable only at 18 months and still rests on a human transgene over an intact mouse Optn background. The knock-in line has the right allele at the right locus but is reported as homozygous. Mouse retina additionally has no macula and the mouse optic nerve head no lamina cribrosa, removing the biomechanical setting in which human glaucomatous cupping develops. The consequence is concrete: neuroprotection results and phenotype-selectivity claims from these lines should not be transferred to patients without independent corroboration.

Proposed experiments

Heterozygous knock-in comparison

optn_heterozygous_knockin_comparison

Characterize heterozygous Optn E50K knock-in mice alongside homozygotes for ganglion cell survival, autophagic flux and outer retinal integrity, to establish whether the ganglion-cell selectivity of human disease is a dosage effect.

Human retinal organoid and post-mortem tissue validation

optn_human_retina_validation

Test whether the autophagic-flux block and any outer-retinal involvement seen in mice are present in OPTN(E50K) human retinal organoids and in post-mortem retina from genotyped patients.

Show evidence (2 references)

PMID:25818176 SUPPORT Model Organism

"This mouse improves the design and phenotype of currently available optineurin mice, which showed high global overexpression."

The authors of the BAC line state explicitly that the pre-existing optineurin mice suffered from high global overexpression and needed improvement, which is the design mismatch this discussion is about.

PMID:20388642 SUPPORT Model Organism

"E50K mice also showed massive apoptosis and degeneration of entire retina, leading to approximately a 28% reduction of the retina thickness."

Quantifies the panretinal degeneration produced by the overexpression model - a whole-retina phenotype rather than the ganglion-cell-selective optic neuropathy of the human disease.

Why do the causative and susceptibility OPTN alleles differ so sharply between populations, and what does that imply for genetic testing?

KNOWLEDGE GAP OPEN optn_allele_population_specificity

Attached to

pathophysiology#OPTN Missense Variant and Optineurin Misfolding

The OPTN alleles reported as risk-conferring or disease-causing in Caucasian cohorts were not detected in Japanese glaucoma patients, while M98K shows a robust association with POAG and NTG in Japanese and other East Asian series and is not replicated in Caucasians. Normal-tension glaucoma is itself more prevalent in East Asian populations. Whether this reflects genuinely different allelic architecture, differing linkage disequilibrium around a shared functional variant, or ascertainment differences between cohorts is unresolved, and it directly affects how an OPTN result should be interpreted in a given patient.

Proposed experiments

Cross-ancestry OPTN sequencing with matched phenotyping

optn_cross_ancestry_sequencing

Sequence OPTN in large, uniformly phenotyped normal-tension glaucoma cohorts across ancestries with shared IOP and disc-imaging protocols, to separate allelic architecture from ascertainment.

Show evidence (1 reference)

PMID:14755458 SUPPORT Human Clinical

"The current results suggest that there may be certain racial differences between Japanese and Caucasians with respect to OPTN genotypes."

The primary observation of population-differing OPTN genotypes that this discussion is about.

Do OPTN-related glaucoma and OPTN-related ALS share one pathological mechanism differing only in the neuron affected, or are they distinct diseases that happen to involve the same gene?

KNOWLEDGE GAP OPEN optn_glaucoma_als_convergence

Attached to

pathophysiology#Impaired Autophagic Flux in Retinal Ganglion Cells

OPTN mutations cause both normal-tension glaucoma and ALS, and TBK1 lesions likewise cause both. In general the glaucoma-associated alleles are missense and the ALS-associated alleles include deletions and nonsense changes, with essentially no overlap - which argues for distinct molecular consequences. Against that, aged Optn E50K knock-in mice develop spinal cord TDP-43 accumulation and motor dysfunction as well as retinal disease, and TDP-43 mishandling is the canonical ALS lesion. Resolving this matters for whether therapeutic results should be expected to transfer between the two diseases.

Show evidence (3 references)

PMID:29875767 SUPPORT Other

"Interestingly, mutations in OPTN, encoding optineurin, are associated with both ALS and glaucoma."

Establishes the shared-gene fact that makes this question worth asking. Evidence source is OTHER because this is a review article.

PMID:29951055 SUPPORT Other

"Glaucoma-associated mutations of OPTN are mostly missense mutations."

Graded PARTIAL: supports the allele-class asymmetry argued in the rationale (glaucoma alleles are predominantly missense) but does not by itself state the ALS allele spectrum. Evidence source is OTHER because this is a review article.

PMID:33723228 SUPPORT Model Organism

"In addition, we also observed increased cytoplasmic TDP-43 in the spinal cord and motor dysfunction in 24-month-old OPTN (E50K) mice, indicating that TDP-43 accumulation may be the common pathological mechanism of glaucoma and amyotrophic lateral sclerosis (ALS)."

The counter-observation: a glaucoma allele producing ALS-like spinal pathology in aged mice, which is the argument for shared mechanism.

⚙

Pathophysiology

6

OPTN Missense Variant and Optineurin Misfolding

A heterozygous missense change in OPTN - most commonly p.Glu50Lys (E50K), the recurrent allele in normal-tension glaucoma pedigrees - alters the biophysical behaviour of optineurin. Mutant OPTN binds TANK-binding kinase 1 (TBK1) abnormally strongly, which blocks the normal oligomerization and solubility that optineurin needs for its intracellular transitions, and the insoluble protein accumulates in the endoplasmic reticulum. Independently, E50K drives formation of covalently cross-linked optineurin oligomers of the kind normally seen only under oxidative stress. This is a toxic gain-of-function lesion rather than simple haploinsufficiency, which is why heterozygosity suffices and why TBK1 is a tractable drug target one step downstream.

protein kinase binding GO:0019901 ↑ INCREASED

Downstream

Impaired Autophagic Flux in Retinal Ganglion Cells The misfolded, TBK1-bound mutant protein is itself the autophagy receptor, so its aberrant state directly disables the flux it should support.

Disrupted Rab8-Dependent Vesicle Trafficking The same substitution abolishes the optineurin-Rab8 interaction that supports Golgi-to-membrane vesicle transport.

Show evidence (3 references)

PMID:23669351 SUPPORT In Vitro

"The E50K mutant strongly interacted with TANK-binding kinase 1 (TBK1), which prohibited the proper oligomerization and solubility of OPTN, both of which are important for OPTN intracellular transition."

Establishes the enhanced E50K-TBK1 interaction and the resulting loss of proper oligomerization and solubility that define this node.

PMID:23669351 SUPPORT In Vitro

"Over-expression of E50K in HEK293 cells indicated accumulation of insoluble OPTN in the endoplasmic reticulum (ER)."

Localizes the insoluble mutant protein to the endoplasmic reticulum.

PMID:24983867 SUPPORT In Vitro

"In cells expressing OPTN bearing the most common glaucoma-associated mutation, E50K, covalent oligomers were formed even without H2O2 stimulation."

Shows that E50K alone drives the covalent cross-linked oligomer state that wild-type optineurin adopts only under oxidative stress, supporting the misfolding characterization of this node.

Impaired Autophagic Flux in Retinal Ganglion Cells

Optineurin is a selective autophagy receptor: it binds polyubiquitinated cargo through its ubiquitin-binding domain and delivers it to nascent autophagosomes through its LC3-interacting region, and it links autophagosomes to lysosomes via myosin VI. Retinal ganglion cells express optineurin highly and, as long-lived post-mitotic neurons with an exceptional axonal maintenance burden, depend heavily on autophagic quality control. Mutant optineurin blocks flux through this pathway. In OPTN(E50K) mice and in E50K-expressing retinal cells, LC3-II and p62/SQSTM1 both accumulate - the signature of a downstream block rather than reduced initiation - and undegraded substrates including TDP-43 aggregate in the cytoplasm. In isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells the same lesion is accompanied by AMPK activation and reduced mTORC1 signalling, and mTOR-independent induction of autophagy restores neurite outgrowth, showing the block is the proximate cause of the neurodegenerative phenotype rather than a bystander. This node conforms to the `disabled_macroautophagy` module's central effector: the failure point here is selective cargo recognition by the receptor itself, not the core ATG machinery, and it is genetic rather than age-associated, but the resulting loss of cytoplasmic quality control is the conserved state that module models.

Retinal Ganglion Cell CL:0000740

Macroautophagy GO:0016236 ↓ DECREASED Autophagosome-Lysosome Fusion GO:0061909 ↓ DECREASED mTORC1 Signalling GO:0038202 ↓ DECREASED

Experimental models

Isogenic OPTN(E50K) human pluripotent stem cell-derived retinal ganglion cells IPSC DERIVED MODEL Human retinal ganglion cells with the disease genotype reproduce the autophagic-lysosomal degradation block, in an isogenic comparison.

Animal models

Optn E50K knock-in mouse (CRISPR/Cas9 point mutation) Mouse recapitulates Autophagic flux is blocked in mutant retina, with the LC3-II/p62 co-accumulation signature and consequent substrate aggregation.

Downstream

Impaired Mitophagy and Mitochondrial Dysfunction Mitophagy is one of the selective-autophagy programmes optineurin serves, so a receptor-level lesion propagates into it.

Retinal Ganglion Cell Apoptosis Loss of autophagic quality control in a long-lived post-mitotic neuron leads to its apoptotic death; forcing flux rescues the phenotype, which is what makes this edge causal rather than correlative.

Show evidence (5 references)

PMID:26302410 SUPPORT In Vitro

"Optineurin was identified as an autophagy receptor that directly interacts with autophagosomal protein, LC3, and ubiquitin."

Establishes the normal autophagy-receptor role of optineurin that this node describes being lost.

PMID:26302410 SUPPORT In Vitro

"Optineurin interacts with a motor protein, myosinVI, and this interaction is involved in mediating fusion of autophagosomes with lysosomes."

Supports the autophagosome-lysosome fusion step annotated on this node as an optineurin-dependent function.

PMID:33723228 SUPPORT Model Organism

"Increased p62/SQSTM1 and LC3-II levels indicated that autophagic flux was inhibited and contributed to TDP-43 aggregation in vivo and in vitro."

Provides the direct flux measurement (LC3-II and p62 both up) behind the DECREASED macroautophagy annotation, in an E50K knock-in mouse and in E50K-expressing retinal cells.

+ 2 more references

Impaired Mitophagy and Mitochondrial Dysfunction

Optineurin is one of the principal mitophagy receptors of the PINK1/Parkin pathway, and it initiates mitophagy by an unconventional route: rather than recruiting FIP200 and the ULK1/2 complex as NDP52, TAX1BP1 and p62 do, OPTN uses TBK1 bound directly to the class III PI3K complex I. Because that initiation step runs through the very kinase whose interaction E50K perturbs, the mitophagy arm is not simply a special case of the general autophagy block but a mechanistically distinct point of vulnerability. Failure to clear damaged mitochondria leaves retinal ganglion cells - among the most energetically demanding neurons in the body, with long unmyelinated intraretinal axons - carrying a dysfunctional mitochondrial pool. This node is curated as an amplifier of, not a substitute for, the autophagic-flux lesion.

Retinal Ganglion Cell CL:0000740

Mitophagy GO:0000423 ↓ DECREASED Mitochondrion Organization GO:0007005 ↕ DYSREGULATED

Downstream

Retinal Ganglion Cell Apoptosis Accumulation of damaged mitochondria in an energetically demanding neuron with long unmyelinated intraretinal axons contributes to its death.

Show evidence (3 references)

PMID:37207627 SUPPORT In Vitro

"Here, we uncover an unconventional path of PINK1/Parkin mitophagy initiation by OPTN that does not begin with FIP200 binding or require the ULK1/2 kinases."

Establishes the distinct, TBK1-dependent route by which optineurin initiates mitophagy, which is the mechanistic basis for treating this as a separate node from bulk autophagy.

PMID:37207627 SUPPORT In Vitro

"Using gene-edited cell lines and in vitro reconstitutions, we show that OPTN utilizes the kinase TBK1, which binds directly to the class III phosphatidylinositol 3-kinase complex I to initiate mitophagy."

Names TBK1 as the initiating kinase for OPTN-driven mitophagy, linking this node back to the E50K-TBK1 lesion in the trigger node.

PMID:26142952 SUPPORT Other

"It is involved in xenophagy, mitophagy, aggrephagy, and tumor suppression."

Review confirming mitophagy as one of the selective-autophagy functions of optineurin. Evidence source is OTHER because this is a review.

Disrupted Rab8-Dependent Vesicle Trafficking

Beyond autophagy, optineurin acts as an effector and adaptor for the Rab8 GTPase, coupling Rab8 to myosin VI and to its GTPase-activating protein TBC1D17 to control Golgi-to-plasma-membrane vesicle transport and transferrin receptor recycling. The E50K substitution disrupts the Optn-Rab8 interaction. This trafficking arm is curated as a modifier rather than a second central effector: it is well demonstrated biochemically and in transgenic mouse retina, but the pathway from disturbed vesicle transport to ganglion cell death is less directly evidenced than the autophagic route.

Retinal Ganglion Cell CL:0000740

Intracellular Protein Transport GO:0006886 ↕ DYSREGULATED

Animal models

E50K optineurin transgenic mouse (global overexpression) Mouse recapitulates The study in which loss of the Optn-Rab8 interaction was first demonstrated as a molecular consequence of E50K.

Downstream

Retinal Ganglion Cell Apoptosis Trafficking failure is reported as a contributor to ganglion cell death, but the intermediate steps between disturbed vesicle transport and apoptosis are not established, hence an indirect edge.

Show evidence (2 references)

PMID:20388642 SUPPORT Model Organism

"At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane."

Directly demonstrates loss of the Optn-Rab8 interaction as a consequence of E50K, in the transgenic mouse study that first reported it.

PMID:29951055 SUPPORT Other

"Glaucoma-associated mutants of OPTN, E50K, and M98K, cause defective vesicle trafficking, autophagy, and signaling that contribute to death of retinal ganglion cells (RGCs)."

Review placing defective vesicle trafficking alongside autophagy as a contributor to retinal ganglion cell death. Evidence source is OTHER because this is a review article.

Retinal Ganglion Cell Apoptosis

Retinal ganglion cells carrying mutant optineurin die by apoptosis. This is the node at which OPTN-related disease rejoins the conserved glaucomatous neurodegeneration captured by the `glaucoma_optic_neuropathy` module - but it is reached from a cell-autonomous proteostatic lesion rather than from the module's trabecular-outflow and elevated-IOP arm, which does not apply to this entity. E50K knock-in mice show reduced numbers of viable ganglion cells and raised cleaved caspase-3 in the retina at intraocular pressures indistinguishable from wild type, and E50K-overexpressing retinal cells show an increased early apoptotic fraction.

Retinal Ganglion Cell CL:0000740

Neuron Apoptotic Process GO:0051402 ↑ INCREASED

Retina UBERON:0000966

Animal models

Optn E50K knock-in mouse (CRISPR/Cas9 point mutation) Mouse recapitulates Ganglion cell loss with apoptotic markers at normal intraocular pressure, from the endogenous mutant allele.

BAC E50K optineurin transgenic mouse (near-physiological expression) Mouse partially recapitulates Mutant optineurin expression accelerates ganglion cell and axon loss above the age-related baseline at near-physiological expression levels.

Downstream

Progressive Glaucomatous Optic Neuropathy at Normal Intraocular Pressure Cumulative ganglion cell and axon loss is what produces the cupping, nerve fibre layer thinning and field loss that define the clinical entity.

Show evidence (4 references)

PMID:26302410 SUPPORT In Vitro

"A glaucoma-associated mutant of optineurin, E50K, impairs autophagy as well as vesicle trafficking, leading to death of retinal cells by apoptosis."

Connects the upstream autophagy and trafficking lesions to apoptotic retinal cell death, which is the claim this node makes.

PMID:33723228 SUPPORT Model Organism

"Loss of RGCs decreased retinal thickness and visual impairment were observed in OPTN (E50K) mice compared with WT mice."

In vivo ganglion cell loss in an E50K knock-in mouse, the animal counterpart of this node.

PMID:33723228 SUPPORT In Vitro

"Moreover, overexpression of E50K OPTN induced R28 cell apoptosis."

Cell-based confirmation that mutant optineurin is sufficient to induce apoptosis in a retinal precursor line.

+ 1 more reference

Progressive Glaucomatous Optic Neuropathy at Normal Intraocular Pressure

Cumulative ganglion cell and axon loss produces the clinical entity: deep optic disc cupping, retinal nerve fibre layer thinning, and progressive visual field loss, with an open and unremarkable drainage angle and intraocular pressures at or below 21 mmHg. The defining feature relative to the rest of the glaucoma family is that this endpoint is reached without the elevated-IOP step: E50K carriers in the Moorfields series had mean presenting and peak diurnal IOP of about 15 and 17 mmHg, and E50K mice develop retinal degeneration at intraocular pressures statistically indistinguishable from wild-type littermates. Relative to mutation-negative normal-tension glaucoma the course is more aggressive - younger age at presentation, deeper cupping and smaller rim area at diagnosis, and a much higher rate of filtration surgery for progressive field loss.

Retinal Ganglion Cell CL:0000740

Optic Nerve UBERON:0000941 Optic Disc UBERON:0001783

Animal models

E50K optineurin transgenic mouse (global overexpression) Mouse partially recapitulates Reproduces the defining feature - retinal ganglion cell and nerve fibre layer loss occurring at normal intraocular pressure - in the correct tissue and with a progressive course.

Show evidence (4 references)

PMID:16043855 SUPPORT Human Clinical

"All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing."

Quantifies the normal intraocular pressures at which the optic neuropathy occurs in E50K carriers, which is the defining claim of this node.

PMID:16043855 SUPPORT Human Clinical

"The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields."

Supports the more aggressive course relative to mutation-negative normal-tension glaucoma asserted in this node.

PMID:23669351 SUPPORT Human Clinical

"The optineurin (OPTN) E50K mutation was first identified in familial primary open-angle glaucoma (POAG), the onset of which is not associated with intraocular pressure (IOP) elevation, and is classified as normal-tension glaucoma (NTG)."

States the IOP-independence of onset that separates this node from the module's elevated-IOP arm.

+ 1 more reference

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

5

Open Angle Glaucoma Ophthalmological HP:0012108

Onset: ADULT; mean 40.8y

Show evidence (2 references)

PMID:11834836 SUPPORT Human Clinical

"In a study of 54 families with autosomal dominantly inherited adult-onset POAG, we identified the causative gene on chromosome 10p14 and designated it OPTN (for "optineurin")."

The gene was identified in families with adult-onset primary open-angle glaucoma, establishing the open-angle phenotype for this entity.

PMID:16043855 SUPPORT Human Clinical

"subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area"

Supports the age-at-presentation figure recorded on the onset descriptor and its significant difference from mutation-negative NTG controls.

Normal Intraocular Pressure at Presentation VERY_FREQUENT Ophthalmological

Show evidence (1 reference)

PMID:16043855 SUPPORT Human Clinical

"All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing."

Reports that all E50K carriers in the series had normal-tension glaucoma with quantified normal presenting and peak diurnal pressures, supporting the VERY_FREQUENT band in this cohort.

Increased Cup-to-Disc Ratio VERY_FREQUENT Ophthalmological HP:0012796

Show evidence (2 references)

PMID:16043855 SUPPORT Human Clinical

"subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area"

Quantifies the cupping in E50K carriers and its significant excess over mutation-negative NTG controls, supporting both the phenotype and the VERY_FREQUENT band.

PMID:37353142 SUPPORT Human Clinical

"Common features of OPTN -associated NTG due to Glu50Lys mutation included early onset of disease with an IOP <21 mm Hg, marked optic disc cupping, and progressive visual field loss"

Independent pedigree series listing marked optic disc cupping among the common features of Glu50Lys disease.

Glaucomatous Visual Field Defect VERY_FREQUENT Ophthalmological HP:0007854

Course: PROGRESSIVE

Show evidence (2 references)

PMID:16043855 SUPPORT Human Clinical

"The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields."

All E50K subjects had progressing visual fields, supporting both the VERY_FREQUENT band and the PROGRESSIVE course.

PMID:37353142 SUPPORT Human Clinical

"progressive visual field loss which appeared to stabilize once an IOP of less than 10 mm Hg was achieved"

Supports the progressive course and the observation about stabilization at very low intraocular pressure quoted in the description.

Abnormal Retinal Nerve Fiber Layer Morphology Ophthalmological HP:0020119

Show evidence (1 reference)

PMID:20388642 SUPPORT Model Organism

"After 16 months, histological abnormalities were exclusively observed in the retina of E50K mutant mice with loss of RGCs and connecting synapses in the peripheral retina leading to a thinning of the nerve fiber layer at the optic nerve head at normal IOP."

Demonstrates nerve fibre layer thinning at normal IOP in the E50K mouse. Graded PARTIAL because this is model-organism evidence standing in for a human phenotype claim.

🧬

Genetic Associations

2

OPTN (Causative)

Gene: OPTN hgnc:17142 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (3 references)

PMID:11834836 SUPPORT Human Clinical

"Sequence alterations in OPTN were found in 16.7% of families with hereditary POAG, including individuals with normal intraocular pressure."

Establishes OPTN sequence alterations as the cause in a defined fraction of hereditary POAG families, including normal-pressure cases.

PMID:11834836 SUPPORT Human Clinical

"Optineurin is expressed in trabecular meshwork, nonpigmented ciliary epithelium, retina, and brain, and we speculate that it plays a neuroprotective role."

Documents the retinal expression that makes a ganglion-cell-autonomous mechanism plausible, and the originally proposed neuroprotective role.

PMID:29951055 SUPPORT Other

"Glaucoma-associated mutations of OPTN are mostly missense mutations."

Supports the statement that the glaucoma-causing OPTN allele class is predominantly missense. Evidence source is OTHER because this is a review article.

Variants (1)

OPTN p.Glu50Lys (E50K) Pathogenic

Gene: OPTN hgnc:17142

The recurrent missense allele of OPTN in normal-tension glaucoma, and the most common glaucoma-associated OPTN mutation. Acts by toxic gain of function: it strengthens the OPTN-TBK1 interaction, renders optineurin insoluble and covalently cross-linked, and blocks autophagic flux.

Show evidence (2 references)

PMID:24983867 SUPPORT In Vitro

"In cells expressing OPTN bearing the most common glaucoma-associated mutation, E50K, covalent oligomers were formed even without H2O2 stimulation."

Identifies E50K as the most common glaucoma-associated OPTN mutation and characterizes its biophysical consequence.

PMID:27693724 SUPPORT Other

"we focus on the OPTN E50K mutation, the most common mutation for NTG"

Independent review confirming E50K as the most common OPTN mutation in normal-tension glaucoma. Evidence source is OTHER because this is a review article.

OPTN p.Met98Lys (M98K) (Risk Factor)

Gene: OPTN hgnc:17142 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:15226658 SUPPORT Human Clinical

"The frequency of the missense Met98Lys variant was higher in the POAG and NTG groups than in the control group (16.9% versus 5%, 15.4% versus 5%; P = 0.009 and P = 0.029, and odds ratio 3.85 and 3.45, respectively, for the dominant effect of the OPTN A allele)."

Quantifies the association of M98K with POAG and NTG in a Japanese case-control series, supporting the SUSCEPTIBILITY typing.

PMID:26302410 SUPPORT In Vitro

"A polymorphism of optineurin, M98K, associated with glaucoma, causes enhanced autophagy leading to transferrin receptor degradation and apoptotic death of retinal cells."

Supports the claim that M98K acts through enhanced rather than impaired autophagy, the opposite direction to E50K.

💊

Medical Actions

4

Intraocular Pressure Lowering

Action: Pharmacotherapy NCIT:C15986

Agent: prostaglandin analogue NCIT:C78568 betaxolol CHEBI:3082 brimonidine CHEBI:3175

All established glaucoma therapy works by lowering intraocular pressure, and that remains the only evidence-based intervention for OPTN-related disease even though the pressure is not elevated to begin with. In a four-generation Glu50Lys pedigree followed for a mean of 17 years, visual field progression appeared to stabilize only once IOP was brought below 10 mmHg, so the target pressure is substantially lower than in ordinary open-angle glaucoma. This is an observational pedigree finding, not a randomized result.

Show evidence (3 references)

PMID:37353142 SUPPORT Human Clinical

"progressive visual field loss which appeared to stabilize once an IOP of less than 10 mm Hg was achieved"

The observation behind the very low target pressure recommended for OPTN-related normal-tension glaucoma.

PMID:27413503 SUPPORT Other

"Betaxolol, brimonidine, prostaglandin analogues, trabeculectomy (in refractory cases), systemic calcium channel blockers (such as nifedipine) and 24-hour monitoring of blood pressure are considered in the management of NTG."

Source for the agent classes bound in therapeutic_agent. Graded PARTIAL and tagged OTHER deliberately: this is a narrative review of normal-tension glaucoma in general, NOT of OPTN-related disease, so it establishes what is used in NTG management and not that any of these agents has OPTN-specific evidence. Calcium channel blockers are named in the quote but deliberately not bound as agents here - they target the vascular-dysregulation model of non-Mendelian NTG, which is not this entity's mechanism.

PMID:27413503 SUPPORT Other

"Treatment is generally aimed to lower IOP by 30% from pre-existing levels to 12-14 mmHg."

The general NTG pressure target, for contrast with the sub-10 mmHg target the OPTN-specific pedigree evidence above supports. Graded PARTIAL because it is a general-NTG figure, not an OPTN-specific one.

Filtration Surgery

Action: Surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Filtering surgery for progressive visual field loss is required far more often in E50K carriers than in mutation-negative normal-tension glaucoma (72.7% versus 25.3% in the Moorfields series). This reflects the aggressive natural history rather than a mutation-specific surgical indication.

Show evidence (1 reference)

PMID:16043855 SUPPORT Human Clinical

"The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003)"

Quantifies the excess rate of filtration surgery in E50K carriers.

TBK1 Inhibition (Investigational)

Action: Pharmacotherapy NCIT:C15986

Agent: amlexanox NCIT:C47395

Because the E50K lesion works through an abnormally strong OPTN-TBK1 interaction, inhibiting TBK1 is the mechanistically obvious intervention. The TBK1 inhibitor BX795 reverses the aberrant insolubility of the E50K protein in cells, and amlexanox has been reported to protect retinal ganglion cells in Optn E50K knock-in mice. INVESTIGATIONAL ONLY - this is preclinical cell and mouse data with no human trial evidence, and it must not be curated or read as established therapy. Only amlexanox is bound in therapeutic_agent. BX795 has no CHEBI or NCIT term, and it is deliberately NOT stood in for by a broad drug class: what matters mechanistically here is TBK1 selectivity, which a class covering every kinase inhibitor does not express. BX795's identity is carried by this description and by the cited evidence instead.

Mechanism Target:

INHIBITS OPTN Missense Variant and Optineurin Misfolding — TBK1 inhibition targets the kinase whose enhanced binding to mutant optineurin produces the insolubility that initiates this pathway.

Show evidence (1 reference)

PMID:23669351 SUPPORT In Vitro

"Treatment with a TBK1 inhibitor, BX795, abrogated the aberrant insolubility of the E50K mutant."

Shows that inhibiting TBK1 reverses the specific molecular defect modeled by the target node.

Show evidence (2 references)

PMID:27693724 SUPPORT Model Organism

"Here we show for the first time that amlexanox protects RGCs in Optn E50K knock-in mice."

Reports retinal ganglion cell protection by a TBK1 inhibitor in an E50K knock-in mouse - the strongest in vivo support for this approach, and still preclinical.

PMID:29951055 SUPPORT Other

"TBK1 protein kinase, which mediates E50K-OPTN and M98K-OPTN induced cell death, is emerging as a potential drug target."

Review identifying TBK1 as an emerging drug target for OPTN-mutant glaucoma. Evidence source is OTHER because this is a review article.

Autophagy Induction (Investigational)

Action: Pharmacotherapy NCIT:C15986

Agent: rapamycin (sirolimus) CHEBI:9168

If the primary lesion is a block in autophagic flux, forcing flux should rescue the cells. Rapamycin reduced TDP-43 aggregation and increased ganglion cell number and visual function in OPTN(E50K) mice, and mTOR-independent autophagy induction restored neurite outgrowth in isogenic OPTN(E50K) human stem cell-derived ganglion cells. INVESTIGATIONAL ONLY - preclinical mouse and human-cell data with no clinical trial evidence. Note also that the human-cell work found mTORC1 signalling already DECREASED in mutant cells, which is an argument against mTOR inhibitors specifically and in favour of mTOR-independent inducers.

Mechanism Target:

ACTIVATES Impaired Autophagic Flux in Retinal Ganglion Cells — Pharmacological induction of autophagy is directed at restoring flux through the pathway blocked by mutant optineurin.

Show evidence (1 reference)

PMID:39425218 SUPPORT In Vitro

"the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN(E50K) RGCs"

Direct rescue of the target node's consequences by inducing autophagy in human OPTN(E50K) retinal ganglion cells.

Show evidence (1 reference)

PMID:33723228 SUPPORT Model Organism

"Moreover, rapamycin increased the RGC number and visual function of E50K mice."

In vivo rescue of ganglion cell number and visual function by an autophagy inducer in an E50K mouse.

🔬

Diagnosis

4

Glaucoma Workup with Documented Normal Intraocular Pressure

The diagnosis is made the same way normal-tension glaucoma is: demonstrate a genuinely glaucomatous optic neuropathy, demonstrate an open anterior chamber angle, and demonstrate that intraocular pressure stays below 21 mmHg. Goldmann applanation tonometry (with diurnal assessment where peaks are suspected), gonioscopy, slit lamp biomicroscopy, optical coherence tomography of the peripapillary nerve fibre layer, and standard automated perimetry are the core investigations. Pachymetry matters because a thin cornea causes tonometry to underestimate the true pressure and so can manufacture an apparent normal-tension case.

Tonometry NCIT:C120543

Show evidence (2 references)

PMID:27413503 SUPPORT Other

"Goldmann applanation tonometry, gonioscopy, slit lamp biomicroscopy, optical coherence tomography and visual field analysis are the main tools of investigation for the diagnosis of NTG."

Names the diagnostic battery this entry records. Evidence source is OTHER because this is a narrative review.

PMID:27413503 SUPPORT Other

"Normal tension glaucoma (NTG) is labelled when typical glaucomatous disc changes, visual field defects and open anterior chamber angles are associated with intraocular pressure (IOP) constantly below 21 mmHg."

Gives the three diagnostic criteria - disc changes, field defects, open angle - together with the sub-21 mmHg pressure requirement. Evidence source is OTHER because this is a narrative review.

Gonioscopy

Gonioscopy establishes that the drainage angle is open, which is what separates this entity and the rest of the open-angle group from angle-closure glaucoma.

Gonioscopy NCIT:C93195

Show evidence (1 reference)

PMID:27413503 SUPPORT Other

"open anterior chamber angles on gonioscopy and maximum intraocular pressure (IOP) below 21 mmHg"

Establishes gonioscopic confirmation of an open angle as part of the diagnostic definition. Evidence source is OTHER because this is a narrative review.

Optical Coherence Tomography of the Retinal Nerve Fiber Layer

OCT quantifies peripapillary retinal nerve fibre layer and macular ganglion cell complex thickness, and is the structural measure by which progression is tracked. It is the clinical readout closest to the pathophysiology curated here, since it measures ganglion cell axon loss directly.

Optical coherence tomography NCIT:C20828

Show evidence (1 reference)

PMID:27413503 SUPPORT Other

"progressive retinal nerve fiber layer thinning, characteristic visual field defects, open anterior chamber angles on gonioscopy"

Identifies progressive nerve fibre layer thinning as a defining, trackable feature. Evidence source is OTHER because this is a narrative review.

OPTN Genetic Testing

Molecular confirmation. A multigene glaucoma panel is generally preferred over isolated OPTN sequencing when the familial variant is unknown, because familial normal-tension glaucoma is genetically heterogeneous and TBK1 copy-number gain - which single-gene sequencing will miss - is a differential cause. Where a pathogenic familial variant is already known, targeted testing of that variant supports cascade screening of relatives, who then need lifelong ophthalmic surveillance because penetrance is age-dependent.

Genetic testing NCIT:C15709

The pre-test probability is low in unselected normal-tension glaucoma (~1% for OPTN), so genetic testing is most informative in familial, early-onset, or otherwise atypical disease.

Show evidence (1 reference)

PMID:37353142 SUPPORT Human Clinical

"Approximately 2% of NTG cases are caused primarily by mutations in single genes, optineurin (OPTN), TANK binding kinase 1 (TKB1), or myocilin (MYOC)."

Establishes the genetic heterogeneity of familial normal-tension glaucoma that motivates panel rather than single-gene testing.

📈

Progression

3

Presymptomatic carrier

Carriers may have entirely normal optic discs and visual fields well into adulthood: seven E50K carriers aged 23-58 years in the Moorfields families had no signs of glaucoma at the time of study. Penetrance is age-dependent, so surveillance rather than reassurance is the correct response to a normal examination in a young carrier.

Show evidence (1 reference)

PMID:16043855 SUPPORT Human Clinical

"In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma."

Documents the presymptomatic carrier phase this record describes.

Established glaucoma at presentation

Presentation is at a mean of about 41 years with already-advanced structural damage - mean cup-disc ratio 0.86 and reduced neuroretinal rim area - which is worse than mutation-negative normal-tension glaucoma at diagnosis. The disease has therefore usually been running silently for some time before it is found.

Show evidence (1 reference)

PMID:16043855 SUPPORT Human Clinical

"subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area"

Quantifies age and structural damage at presentation for this phase.

Progressive visual field loss

All E50K patients in the Moorfields series had progressing visual fields, and nearly three quarters required filtration surgery for that progression. In a separate four-generation pedigree followed for a mean of 17 years, progression appeared to stabilize once intraocular pressure was brought below 10 mmHg - the practical basis for a very low target pressure. Ganglion cell loss is irreversible, so treatment preserves remaining function rather than recovering lost vision.

Show evidence (2 references)

PMID:16043855 SUPPORT Human Clinical

"The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields."

Establishes universal progression and the resulting surgical rate in this phase.

PMID:37353142 SUPPORT Human Clinical

"progressive visual field loss which appeared to stabilize once an IOP of less than 10 mm Hg was achieved"

Supports the stabilization-at-very-low-pressure observation recorded for this phase.

📊

Prevalence

2

Familial adult-onset primary open-angle glaucoma (54 pedigrees, gene-discovery cohort)

Unknown Unknown

Not a population prevalence. This is the proportion of hereditary POAG families carrying an OPTN sequence alteration in the original gene-discovery cohort (16.7%), an ascertainment-enriched familial series; later unselected cohorts give far lower figures (see the normal-tension glaucoma record below). Recorded here because it is the number most often quoted for this entity and is frequently misread as a population figure.

Show evidence (1 reference)

PMID:11834836 SUPPORT Human Clinical

"Sequence alterations in OPTN were found in 16.7% of families with hereditary POAG, including individuals with normal intraocular pressure."

Source of the 16.7%-of-families figure and of the observation that carriers include individuals with normal intraocular pressure.

Primary open-angle glaucoma with IOP 21 mmHg or less (normal tension glaucoma)

Unknown Unknown

OPTN mutation accounts for roughly 1% of normal-tension glaucoma; OPTN, TBK1 and MYOC together account for approximately 2% of NTG cases. This is a fraction-of-cases figure, not a population rate, so no rate_per_100000 is recorded.

Show evidence (2 references)

PMID:31238079 SUPPORT Human Clinical

"while mutations in OPTN, TBK1, and MYOC each cause ∼1% of POAG with IOP ≤21 mmHg, i.e. normal tension glaucoma"

Gives the ~1% share of normal-tension glaucoma attributable to OPTN mutation.

PMID:37353142 SUPPORT Human Clinical

"Approximately 2% of NTG cases are caused primarily by mutations in single genes, optineurin (OPTN), TANK binding kinase 1 (TKB1), or myocilin (MYOC)."

Independent review giving the combined single-gene share of NTG, which bounds the OPTN-specific figure.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from OPTN-related Open Angle Glaucoma:

Non-Mendelian normal tension glaucoma

Overlapping Features The great majority of normal-tension glaucoma has no single-gene cause. Vascular and haemodynamic factors dominate the proposed pathogenesis - chronic low ocular perfusion, Raynaud phenomenon, migraine, nocturnal systemic hypotension, and over-treated systemic hypertension. Because single-gene disease accounts for only about 2% of normal-tension glaucoma, this is by far the most likely diagnosis in an unselected patient, and it is what an OPTN-related diagnosis has to be positively distinguished from.

Distinguishing Features

Absence of a pathogenic OPTN, TBK1 or MYOC variant; typically older age at presentation than the E50K mean of about 41 years, less severe cupping at diagnosis, and a lower rate of progression to filtration surgery. Vasospastic and nocturnal-hypotension features are commonly present.

Show evidence (1 reference)

PMID:27413503 SUPPORT Other

"Chronic low vascular perfusion, Raynaud's phenomenon, migraine, nocturnal systemic hypotension and over-treated systemic hypertension are the main causes of normal tension glaucoma."

Names the non-genetic causal factors that characterize the far more common non-Mendelian form. Evidence source is OTHER because this is a narrative review.

Primary open angle glaucoma with unrecognized intraocular pressure peaks

Overlapping Features Ordinary high-tension open-angle glaucoma can masquerade as normal-tension disease when the pressure elevation is intermittent and missed by office-hours tonometry, or when a thin cornea causes applanation tonometry to underestimate the true pressure. This is a measurement artefact rather than a distinct disease, but it is the commonest reason a normal-tension label is wrong.

Distinguishing Features

Diurnal or nocturnal tonometry revealing pressure above 21 mmHg; pachymetry showing a thin central cornea that has caused underestimation. Normal-tension patients also show wider diurnal pressure fluctuation than healthy individuals, so a single normal reading settles nothing.

Show evidence (1 reference)

PMID:27413503 SUPPORT Other

"IOP spikes may occur at night, and thus IOPs measured during office hours may miss nocturnal spikes in many patients."

States the measurement failure mode that produces this differential. Evidence source is OTHER because this is a narrative review.

Non-glaucomatous optic neuropathy

Overlapping Features Compressive, ischaemic, inflammatory, hereditary (e.g. OPA1-related dominant optic atrophy) and mitochondrial optic neuropathies can produce optic disc changes and visual field loss without glaucoma. This matters for an OPTN entry in particular, because a diagnosis reached partly on the grounds of "glaucoma at normal pressure" has already given up the pressure criterion and rests more heavily on the pattern of disc and field change.

Distinguishing Features

Optic disc pallor exceeding cupping, marked dyschromatopsia, field defects respecting the vertical meridian, rapid decline, pain, or accompanying neurological signs - any of which should prompt neuroimaging and a neuro-ophthalmic assessment rather than glaucoma management.

📊

Related Datasets

2

Differential gene expression and pathway analysis by RNA sequencing in human OPTN(E50K) retinal ganglion cells geo:GSE145069

RNA-seq of human pluripotent stem cell-derived retinal ganglion cells carrying the OPTN(E50K) mutation versus isogenic controls. Genotype- and cell-type-specific for this entity: the disease allele in the disease cell type, in a human system.

human BULK RNA SEQ n=8

PMID:32531194

Located by GEO DataSets search on "optineurin E50K" rather than on the disease name; accession, title, sample count and organism are GEO's own values, retrieved 2026-08-20. Relevance triage: this is one of only two accessions found that are specific to the OPTN(E50K) genotype rather than to glaucoma generally - a disease-name search returns trabecular meshwork and generic POAG datasets that resolve perfectly but are about the wrong entity. Carries no evidence block: an evidence item needs an exact quote from the cited abstract, and this record's provenance is the repository metadata plus its own linked publication.

Differential gene expression and pathway analysis by RNA sequencing in human OPTN(E50K) astrocytes geo:GSE173129

RNA-seq of human stem cell-derived astrocytes carrying OPTN(E50K), from the study of non-cell-autonomous contributions to ganglion cell degeneration. Complements the ganglion-cell dataset above by covering the glial side of the same genotype.

human BULK RNA SEQ n=8

PMID:35714595

Located by GEO DataSets search on "optineurin E50K"; accession, title, sample count and organism are GEO's own values, retrieved 2026-08-20. Note that the astrocyte arm is NOT modeled in this entry's pathophysiology, which is curated as a cell-autonomous ganglion cell lesion; a non-cell-autonomous glial contribution is plausible but not yet curated here. Carries no evidence block for the same reason as the record above.

🧫

Experimental Models

1

Isogenic OPTN(E50K) human pluripotent stem cell-derived retinal ganglion cells IPSC_DERIVED_MODEL

Human pluripotent stem cell lines in isogenic pairs - patient-derived iPSCs with the E50K mutation corrected, and an H7 embryonic line with E50K introduced by CRISPR/Cas9 - differentiated through retinal organoids into purified retinal ganglion cells. Because the comparison is isogenic, the phenotype is attributable to the OPTN genotype rather than to line background, and because the cells are human ganglion cells it addresses the species limitations of the mouse models directly. Mutant cells show impaired autophagic-lysosomal degradation, AMPK activation, reduced mTORC1 signalling and neurodegenerative features; mTOR-independent autophagy induction rescues neurite outgrowth.

Pathograph links

Impaired Autophagic Flux in Retinal Ganglion Cells recapitulates fidelity: high Human retinal ganglion cells with the disease genotype reproduce the autophagic-lysosomal degradation block, in an isogenic comparison.

Limitations: hPSC-derived retinal ganglion cells are developmentally immature relative to the adult neurons that degenerate in a disease of middle age, and they are cultured without the optic nerve head, lamina cribrosa, glia and vasculature of the intact eye. The model therefore speaks to the cell-autonomous proteostatic lesion, not to the tissue-level neuropathy.

Readouts

Autophagic-lysosomal degradation and mTORC1 signalling

Direction: DECREASED

Interpretation: Reduced degradative flux with concurrent AMPK activation and lowered mTORC1 signalling in mutant human ganglion cells.

Show evidence (1 reference)

PMID:39425218 SUPPORT In Vitro

"We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor AMPK, along with subsequent neurodegeneration in OPTN(E50K) RGCs differentiated from hPSCs"

Reports both measurements recorded in this readout.

Neurite outgrowth after mTOR-independent autophagy induction

Direction: RESTORED

Interpretation: Rescue on forcing flux, which is what makes the flux block causal for the degenerative phenotype rather than merely correlated with it.

Show evidence (1 reference)

PMID:39425218 SUPPORT In Vitro

"the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN(E50K) RGCs"

Reports the rescue that this readout measures.

Show evidence (1 reference)

PMID:39425218 SUPPORT In Vitro

"Taken together, these results highlighted that autophagy disruption resulted in increased autophagic demand which was associated with downregulated signaling through mTORC1, contributing to the degeneration of RGCs."

The study's own conclusion that this human model demonstrates the autophagy-disruption node it is linked to.

Show evidence (1 reference)

PMID:39425218 SUPPORT In Vitro

"we leveraged an isogenic hPSC model with a glaucoma-associated mutation in the Optineurin (OPTN) protein, which plays a prominent role in autophagy"

Establishes the isogenic human stem-cell model described here.

🐁

Animal Models

3

Optn E50K knock-in mouse (CRISPR/Cas9 point mutation)

A CRISPR/Cas9 point-mutation knock-in mouse carrying the human-equivalent E50K change at the endogenous Optn locus - the closest genetic match to the human disease among the available models, since it avoids the supraphysiological expression of the transgenic lines. It shows retinal ganglion cell loss, retinal thinning, reduced visual function and raised cleaved caspase-3, together with blocked autophagic flux and cytoplasmic TDP-43 accumulation, at intraocular pressures indistinguishable from wild-type littermates. Aged animals also develop spinal cord TDP-43 pathology and motor dysfunction, mirroring the OPTN link to ALS.

Species

Mouse

Genotype

Optn p.Glu50Lys knock-in

Publication

PMID:33723228

Pathograph links

Retinal Ganglion Cell Apoptosis recapitulates fidelity: high Ganglion cell loss with apoptotic markers at normal intraocular pressure, from the endogenous mutant allele.

Limitations: The reported animals are homozygous for the knock-in change, whereas human disease is heterozygous, so gene dosage is not matched. Mouse retina lacks a macula and the mouse optic nerve head has no lamina cribrosa, so the biomechanical context of human glaucomatous cupping is absent.

Readouts

Viable retinal ganglion cell count (NeuN immunolabelling)

Direction: DECREASED

Interpretation: Fewer surviving ganglion cells in mutant retina, the cellular correlate of this node.

Show evidence (1 reference)

PMID:33723228 SUPPORT Model Organism

"Loss of RGCs decreased retinal thickness and visual impairment were observed in OPTN (E50K) mice compared with WT mice."

Reports the ganglion cell loss and retinal thinning that this readout measures.

Show evidence (1 reference)

PMID:33723228 SUPPORT Model Organism

"The glaucoma-associated E50K mutation in optineurin (OPTN) is known to affect autophagy and cause the apoptosis of retinal ganglion cells (RGCs)"

Establishes that this model is informative for the ganglion cell apoptosis node it is linked to.

Impaired Autophagic Flux in Retinal Ganglion Cells recapitulates fidelity: high Autophagic flux is blocked in mutant retina, with the LC3-II/p62 co-accumulation signature and consequent substrate aggregation.

Limitations: TDP-43 is the substrate whose accumulation was measured; it is a well-motivated readout given the shared OPTN link to ALS, but it is not established that TDP-43 mishandling is the ganglion-cell-relevant consequence of the flux block in human disease.

Readouts

Retinal p62/SQSTM1 and LC3-II protein levels

Direction: INCREASED

Interpretation: Simultaneous accumulation of an autophagy receptor substrate (p62) and of lipidated LC3 indicates a block in flux rather than reduced autophagosome formation.

Show evidence (1 reference)

PMID:33723228 SUPPORT Model Organism

"Increased p62/SQSTM1 and LC3-II levels indicated that autophagic flux was inhibited and contributed to TDP-43 aggregation in vivo and in vitro."

Reports exactly the two protein measurements and the flux interpretation recorded in this readout.

Show evidence (1 reference)

PMID:33723228 SUPPORT Model Organism

"In this study, we investigated whether the OPTN (E50K) mutation caused TDP-43 aggregation by disrupting autophagy in vivo and in vitro."

States that this model was built and used to interrogate the autophagy-disruption node it is linked to.

Show evidence (1 reference)

PMID:33723228 SUPPORT Model Organism

"OPTN (E50K) mutant mice were generated and analysed for genotype and phenotype."

Establishes the existence and characterization of the knock-in model described here.

E50K optineurin transgenic mouse (global overexpression)

The first optineurin glaucoma mouse: transgenic global overexpression of E50K-mutant optineurin, alongside wild-type and other mutant constructs as controls. At 16 months, histological abnormalities were confined to the retina in the E50K line, with ganglion cell and synapse loss, nerve fibre layer thinning at the optic nerve head, and about a 28% reduction in retinal thickness - all at normal intraocular pressure. It is also the study that first showed E50K disrupts the Optn-Rab8 interaction.

Species

Mouse

Genotype

Transgenic overexpression of E50K-mutated optineurin

Publication

PMID:20388642

Pathograph links

Progressive Glaucomatous Optic Neuropathy at Normal Intraocular Pressure partially recapitulates fidelity: moderate Reproduces the defining feature - retinal ganglion cell and nerve fibre layer loss occurring at normal intraocular pressure - in the correct tissue and with a progressive course.

Limitations: The phenotype extends to massive apoptosis and degeneration of the entire retina with roughly 28% overall retinal thinning, which is a panretinal degeneration rather than the ganglion-cell-selective optic neuropathy seen in patients. A later study attributes this to the high global overexpression of the transgene and reports diffuse loss of photoreceptors and non-RGC cells, features not observed in human POAG. Selectivity claims should not be drawn from this line.

Readouts

Retinal nerve fiber layer thickness at the optic nerve head

Direction: DECREASED

Interpretation: Structural correlate of ganglion cell axon loss, measured at normal intraocular pressure.

Show evidence (1 reference)

PMID:20388642 SUPPORT Model Organism

"After 16 months, histological abnormalities were exclusively observed in the retina of E50K mutant mice with loss of RGCs and connecting synapses in the peripheral retina leading to a thinning of the nerve fiber layer at the optic nerve head at normal IOP."

Reports the nerve fibre layer thinning at normal IOP that this readout measures.

Show evidence (1 reference)

PMID:20388642 SUPPORT Model Organism

"These data suggest that alternation of the Optn sequence can initiate significant retinal degeneration in mice."

The authors' own summary claim for this model. Graded PARTIAL because the claim is for retinal degeneration generally rather than for the ganglion-cell-selective optic neuropathy this node describes, which is exactly the limitation recorded on the link.

Disrupted Rab8-Dependent Vesicle Trafficking recapitulates fidelity: moderate The study in which loss of the Optn-Rab8 interaction was first demonstrated as a molecular consequence of E50K.

Limitations: The interaction data are biochemical and were obtained under the same overexpression conditions that produce the non-physiological retinal phenotype, so the quantitative degree of trafficking disruption at endogenous expression levels is not established.

Show evidence (1 reference)

PMID:20388642 SUPPORT Model Organism

"At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane."

This is the study that established the trafficking lesion, so it is by construction informative for the node it is linked to.

Show evidence (1 reference)

PMID:20388642 SUPPORT Model Organism

"Here, we describe the phenotypic characteristics of transgenic mice overexpressing wild-type (Wt) or mutated optineurin (Optn)."

Establishes the transgenic overexpression design of this model.

BAC E50K optineurin transgenic mouse (near-physiological expression)

A bacterial artificial chromosome transgenic line carrying the human optineurin locus with its own promoter, designed specifically to avoid the global overexpression that made the earlier transgenic line degenerate panretinally. At 18 months, mutant animals show enhanced axonal degeneration and reduced ganglion cell survival over the age-related decline seen in non-transgenic controls, with visual evoked potentials revealing a specific contrast-sensitivity deficit.

Species

Mouse

Genotype

BAC transgenic human optineurin locus carrying E50K

Publication

PMID:25818176

Pathograph links

Retinal Ganglion Cell Apoptosis partially recapitulates fidelity: moderate Mutant optineurin expression accelerates ganglion cell and axon loss above the age-related baseline at near-physiological expression levels.

Limitations: The effect is an enhancement of an age-related decline that also occurs in controls rather than a discrete disease phenotype, and it is detected only at 18 months, so the model has a narrow window and a small dynamic range. Human transgene expression sits on an intact mouse Optn background, so this is an overexpression-of-mutant rather than a true heterozygous knock-in genotype.

Readouts

Healthy optic nerve axon and retinal ganglion cell counts

Direction: DECREASED

Interpretation: Mutant-specific excess loss of axons and ganglion cells over the age-matched non-transgenic decline.

Show evidence (1 reference)

PMID:25818176 SUPPORT Model Organism

"Although both 18-month-old optineurin and nontransgenic control mice showed an age-related decrease in healthy axons and RGCs, the expression of mutant optineurin enhanced axonal degeneration and decreased RGC survival."

Reports both the shared age-related decline and the mutant-specific excess that this readout measures.

Contrast sensitivity by visual evoked potential

Direction: DECREASED

Interpretation: Functional correlate of ganglion cell loss in this model.

Show evidence (1 reference)

PMID:25818176 SUPPORT Model Organism

"Mouse visual function was determined using visual evoked potentials, which revealed specific visual impairment in contrast sensitivity."

Reports the visual evoked potential contrast-sensitivity deficit that this readout measures.

Show evidence (1 reference)

PMID:25818176 SUPPORT Model Organism

"The E50K optineurin transgenic mouse described here exhibited clinical features of POAG and may be useful for mechanistic dissection of POAG and therapeutic development."

The authors' own claim for the model's informativeness. Graded PARTIAL because "may be useful" is a prospective claim and the observed effect is an increment on an age-related decline seen in controls too.

Show evidence (1 reference)

PMID:25818176 SUPPORT Model Organism

"To gain mechanistic insights, we developed a novel mouse model based on a mutation in human optineurin associated with hereditary, low-pressure POAG."

Establishes the model and its design intent as a low-pressure POAG model.

{ }

Source YAML

click to show

name: OPTN-related Open Angle Glaucoma
creation_date: "2026-08-20T00:00:00Z"
category: Mendelian
parents:
- Glaucoma
disease_term:
  preferred_term: OPTN-related open angle glaucoma
  term:
    id: MONDO:0100553
    label: OPTN-related open angle glaucoma
synonyms:
- "glaucoma 1, open angle, E"
- GLC1E
- OPTN-related normal tension glaucoma
- optineurin-associated normal tension glaucoma
description: >
  Adult-onset open-angle glaucoma caused by heterozygous variants in optineurin
  (OPTN, the GLC1E locus on chromosome 10p14), inherited as an autosomal
  dominant Mendelian trait. OPTN was the second gene identified as a Mendelian
  cause of primary open-angle glaucoma, and the recurrent p.Glu50Lys (E50K)
  missense change is by far its best-characterized allele. What distinguishes
  this entity from the trabecular-outflow glaucomas is that the optic
  neuropathy develops at intraocular pressures within the statistically normal
  range: affected individuals characteristically present with normal-tension
  glaucoma, and the disease-causing lesion sits in the retinal ganglion cell
  rather than in the aqueous drainage apparatus. Mutant optineurin, an
  autophagy receptor, binds TBK1 abnormally tightly, becomes insoluble and
  covalently cross-linked, and blocks autophagic-lysosomal flux and
  OPTN-dependent mitophagy in retinal ganglion cells, driving their apoptotic
  loss and a progressive glaucomatous optic neuropathy. Compared with
  mutation-negative normal-tension glaucoma, E50K carriers present younger,
  with deeper optic disc cupping and a much higher rate of progression to
  filtration surgery. This entry is scoped to the OPTN-caused Mendelian entity
  and deliberately does not re-derive the generic IOP-driven adult POAG content
  held in `Glaucoma.yaml`; the shared downstream neurodegeneration is expressed
  by conformance to the `glaucoma_optic_neuropathy` module rather than by
  duplicating its outflow arm, which does not apply here.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    OPTN-related glaucoma segregates as an autosomal dominant trait in the
    multigeneration pedigrees in which the gene was discovered and in
    subsequently reported E50K families. Penetrance is age-dependent and
    incomplete at younger ages: in the Moorfields series seven E50K carriers
    aged 23-58 years had normal discs and fields at the time of study, so an
    unaffected examination in a young carrier does not exclude later disease.
  evidence:
  - reference: PMID:11834836
    reference_title: "Adult-onset primary open-angle glaucoma caused by mutations in optineurin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a study of 54 families with autosomal dominantly inherited adult-onset POAG, we identified the causative gene on chromosome 10p14 and designated it OPTN (for \"optineurin\")."
    explanation: >
      The gene-discovery study established OPTN as the causative gene in
      autosomal dominantly inherited adult-onset POAG pedigrees.
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma."
    explanation: >
      Documents age-dependent, incomplete penetrance among carriers in the two
      studied families, supporting the penetrance caveat in the description.
prevalence:
- population: Familial adult-onset primary open-angle glaucoma (54 pedigrees, gene-discovery cohort)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >
    Not a population prevalence. This is the proportion of hereditary POAG
    families carrying an OPTN sequence alteration in the original gene-discovery
    cohort (16.7%), an ascertainment-enriched familial series; later unselected
    cohorts give far lower figures (see the normal-tension glaucoma record
    below). Recorded here because it is the number most often quoted for this
    entity and is frequently misread as a population figure.
  evidence:
  - reference: PMID:11834836
    reference_title: "Adult-onset primary open-angle glaucoma caused by mutations in optineurin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence alterations in OPTN were found in 16.7% of families with hereditary POAG, including individuals with normal intraocular pressure."
    explanation: >
      Source of the 16.7%-of-families figure and of the observation that
      carriers include individuals with normal intraocular pressure.
- population: Primary open-angle glaucoma with IOP 21 mmHg or less (normal tension glaucoma)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >
    OPTN mutation accounts for roughly 1% of normal-tension glaucoma; OPTN,
    TBK1 and MYOC together account for approximately 2% of NTG cases. This is a
    fraction-of-cases figure, not a population rate, so no rate_per_100000 is
    recorded.
  evidence:
  - reference: PMID:31238079
    reference_title: "Mendelian genes in primary open angle glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "while mutations in OPTN, TBK1, and MYOC each cause ∼1% of POAG with IOP ≤21 mmHg, i.e. normal tension glaucoma"
    explanation: >
      Gives the ~1% share of normal-tension glaucoma attributable to OPTN
      mutation.
  - reference: PMID:37353142
    reference_title: "Familial normal tension glaucoma genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 2% of NTG cases are caused primarily by mutations in single genes, optineurin (OPTN), TANK binding kinase 1 (TKB1), or myocilin (MYOC)."
    explanation: >
      Independent review giving the combined single-gene share of NTG, which
      bounds the OPTN-specific figure.
pathophysiology:
- name: OPTN Missense Variant and Optineurin Misfolding
  biological_scale: MOLECULAR
  role: trigger
  description: >
    A heterozygous missense change in OPTN - most commonly p.Glu50Lys (E50K),
    the recurrent allele in normal-tension glaucoma pedigrees - alters the
    biophysical behaviour of optineurin. Mutant OPTN binds TANK-binding kinase 1
    (TBK1) abnormally strongly, which blocks the normal oligomerization and
    solubility that optineurin needs for its intracellular transitions, and the
    insoluble protein accumulates in the endoplasmic reticulum. Independently,
    E50K drives formation of covalently cross-linked optineurin oligomers of the
    kind normally seen only under oxidative stress. This is a toxic
    gain-of-function lesion rather than simple haploinsufficiency, which is why
    heterozygosity suffices and why TBK1 is a tractable drug target one step
    downstream.
  molecular_functions:
  - preferred_term: protein kinase binding
    term:
      id: GO:0019901
      label: protein kinase binding
    modifier: INCREASED
  evidence:
  - reference: PMID:23669351
    reference_title: "Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The E50K mutant strongly interacted with TANK-binding kinase 1 (TBK1), which prohibited the proper oligomerization and solubility of OPTN, both of which are important for OPTN intracellular transition."
    explanation: >
      Establishes the enhanced E50K-TBK1 interaction and the resulting loss of
      proper oligomerization and solubility that define this node.
  - reference: PMID:23669351
    reference_title: "Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Over-expression of E50K in HEK293 cells indicated accumulation of insoluble OPTN in the endoplasmic reticulum (ER)."
    explanation: >
      Localizes the insoluble mutant protein to the endoplasmic reticulum.
  - reference: PMID:24983867
    reference_title: "Oligomerization of optineurin and its oxidative stress- or E50K mutation-driven covalent cross-linking: possible relationship with glaucoma pathology."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In cells expressing OPTN bearing the most common glaucoma-associated mutation, E50K, covalent oligomers were formed even without H2O2 stimulation."
    explanation: >
      Shows that E50K alone drives the covalent cross-linked oligomer state
      that wild-type optineurin adopts only under oxidative stress, supporting
      the misfolding characterization of this node.
  downstream:
  - target: Impaired Autophagic Flux in Retinal Ganglion Cells
    causal_link_type: DIRECT
    description: >
      The misfolded, TBK1-bound mutant protein is itself the autophagy
      receptor, so its aberrant state directly disables the flux it should
      support.
    evidence:
    - reference: PMID:26302410
      reference_title: "Defects in autophagy caused by glaucoma-associated mutations in optineurin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "A glaucoma-associated mutant of optineurin, E50K, impairs autophagy as well as vesicle trafficking, leading to death of retinal cells by apoptosis."
      explanation: >
        States the E50K-to-impaired-autophagy step that this edge asserts.
  - target: Disrupted Rab8-Dependent Vesicle Trafficking
    causal_link_type: DIRECT
    description: >
      The same substitution abolishes the optineurin-Rab8 interaction that
      supports Golgi-to-membrane vesicle transport.
    evidence:
    - reference: PMID:20388642
      reference_title: "Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane."
      explanation: >
        Directly evidences the E50K-to-Rab8-disruption step that this edge
        asserts.
- name: Impaired Autophagic Flux in Retinal Ganglion Cells
  conforms_to: "disabled_macroautophagy#Failure of Cytoplasmic Quality Control"
  biological_scale: CELLULAR
  role: central_effector
  description: >
    Optineurin is a selective autophagy receptor: it binds polyubiquitinated
    cargo through its ubiquitin-binding domain and delivers it to nascent
    autophagosomes through its LC3-interacting region, and it links
    autophagosomes to lysosomes via myosin VI. Retinal ganglion cells express
    optineurin highly and, as long-lived post-mitotic neurons with an
    exceptional axonal maintenance burden, depend heavily on autophagic
    quality control. Mutant optineurin blocks flux through this pathway.
    In OPTN(E50K) mice and in E50K-expressing retinal cells, LC3-II and
    p62/SQSTM1 both accumulate - the signature of a downstream block rather
    than reduced initiation - and undegraded substrates including TDP-43
    aggregate in the cytoplasm. In isogenic OPTN(E50K) human stem cell-derived
    retinal ganglion cells the same lesion is accompanied by AMPK activation
    and reduced mTORC1 signalling, and mTOR-independent induction of autophagy
    restores neurite outgrowth, showing the block is the proximate cause of the
    neurodegenerative phenotype rather than a bystander. This node conforms to
    the `disabled_macroautophagy` module's central effector: the failure point
    here is selective cargo recognition by the receptor itself, not the core
    ATG machinery, and it is genetic rather than age-associated, but the
    resulting loss of cytoplasmic quality control is the conserved state that
    module models.
  cell_types:
  - preferred_term: Retinal Ganglion Cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  biological_processes:
  - preferred_term: Macroautophagy
    term:
      id: GO:0016236
      label: macroautophagy
    modifier: DECREASED
  - preferred_term: Autophagosome-Lysosome Fusion
    term:
      id: GO:0061909
      label: autophagosome-lysosome fusion
    modifier: DECREASED
  - preferred_term: mTORC1 Signalling
    term:
      id: GO:0038202
      label: TORC1 signaling
    modifier: DECREASED
  evidence:
  - reference: PMID:26302410
    reference_title: "Defects in autophagy caused by glaucoma-associated mutations in optineurin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Optineurin was identified as an autophagy receptor that directly interacts with autophagosomal protein, LC3, and ubiquitin."
    explanation: >
      Establishes the normal autophagy-receptor role of optineurin that this
      node describes being lost.
  - reference: PMID:26302410
    reference_title: "Defects in autophagy caused by glaucoma-associated mutations in optineurin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Optineurin interacts with a motor protein, myosinVI, and this interaction is involved in mediating fusion of autophagosomes with lysosomes."
    explanation: >
      Supports the autophagosome-lysosome fusion step annotated on this node
      as an optineurin-dependent function.
  - reference: PMID:33723228
    reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Increased p62/SQSTM1 and LC3-II levels indicated that autophagic flux was inhibited and contributed to TDP-43 aggregation in vivo and in vitro."
    explanation: >
      Provides the direct flux measurement (LC3-II and p62 both up) behind the
      DECREASED macroautophagy annotation, in an E50K knock-in mouse and in
      E50K-expressing retinal cells.
  - reference: PMID:39425218
    reference_title: "Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor AMPK, along with subsequent neurodegeneration in OPTN(E50K) RGCs differentiated from hPSCs"
    explanation: >
      Human isogenic stem-cell-derived retinal ganglion cell evidence for both
      the autophagic-lysosomal block and the reduced mTORC1 signalling
      annotated on this node.
  - reference: PMID:31238079
    reference_title: "Mendelian genes in primary open angle glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in OPTN and TBK1 cause a dysregulation of autophagy which may directly cause retinal ganglion cell damage and normal tension glaucoma."
    explanation: >
      States the autophagy-to-RGC-damage causal chain at the level of the human
      disease, complementing the cellular and mouse evidence above.
  downstream:
  - target: Impaired Mitophagy and Mitochondrial Dysfunction
    causal_link_type: DIRECT
    description: >
      Mitophagy is one of the selective-autophagy programmes optineurin
      serves, so a receptor-level lesion propagates into it.
    evidence:
    - reference: PMID:26142952
      reference_title: "Optineurin: The autophagy connection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "It is involved in xenophagy, mitophagy, aggrephagy, and tumor suppression."
      explanation: >
        Places mitophagy among the optineurin-dependent selective-autophagy
        programmes, which is what makes this edge follow. Evidence source is
        OTHER because this is a review.
  - target: Retinal Ganglion Cell Apoptosis
    causal_link_type: DIRECT
    description: >
      Loss of autophagic quality control in a long-lived post-mitotic neuron
      leads to its apoptotic death; forcing flux rescues the phenotype, which
      is what makes this edge causal rather than correlative.
    evidence:
    - reference: PMID:26302410
      reference_title: "Defects in autophagy caused by glaucoma-associated mutations in optineurin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Thus, an optimum level of optineurin-mediated autophagy is crucial for survival of retinal cells, and impaired autophagy is likely to contribute to glaucoma pathogenesis."
      explanation: >
        States the autophagy-to-retinal-cell-survival dependency that this
        edge asserts.
    - reference: PMID:33723228
      reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Moreover, rapamycin increased the RGC number and visual function of E50K mice."
      explanation: >
        Rescue by an autophagy inducer, the intervention evidence that the
        flux block is causal for ganglion cell loss rather than a bystander.
- name: Impaired Mitophagy and Mitochondrial Dysfunction
  biological_scale: CELLULAR
  role: amplifier
  description: >
    Optineurin is one of the principal mitophagy receptors of the PINK1/Parkin
    pathway, and it initiates mitophagy by an unconventional route: rather than
    recruiting FIP200 and the ULK1/2 complex as NDP52, TAX1BP1 and p62 do,
    OPTN uses TBK1 bound directly to the class III PI3K complex I. Because that
    initiation step runs through the very kinase whose interaction E50K
    perturbs, the mitophagy arm is not simply a special case of the general
    autophagy block but a mechanistically distinct point of vulnerability.
    Failure to clear damaged mitochondria leaves retinal ganglion cells -
    among the most energetically demanding neurons in the body, with long
    unmyelinated intraretinal axons - carrying a dysfunctional mitochondrial
    pool. This node is curated as an amplifier of, not a substitute for, the
    autophagic-flux lesion.
  cell_types:
  - preferred_term: Retinal Ganglion Cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  biological_processes:
  - preferred_term: Mitophagy
    term:
      id: GO:0000423
      label: mitophagy
    modifier: DECREASED
  - preferred_term: Mitochondrion Organization
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:37207627
    reference_title: "Unconventional initiation of PINK1/Parkin mitophagy by Optineurin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we uncover an unconventional path of PINK1/Parkin mitophagy initiation by OPTN that does not begin with FIP200 binding or require the ULK1/2 kinases."
    explanation: >
      Establishes the distinct, TBK1-dependent route by which optineurin
      initiates mitophagy, which is the mechanistic basis for treating this as
      a separate node from bulk autophagy.
  - reference: PMID:37207627
    reference_title: "Unconventional initiation of PINK1/Parkin mitophagy by Optineurin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using gene-edited cell lines and in vitro reconstitutions, we show that OPTN utilizes the kinase TBK1, which binds directly to the class III phosphatidylinositol 3-kinase complex I to initiate mitophagy."
    explanation: >
      Names TBK1 as the initiating kinase for OPTN-driven mitophagy, linking
      this node back to the E50K-TBK1 lesion in the trigger node.
  - reference: PMID:26142952
    reference_title: "Optineurin: The autophagy connection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is involved in xenophagy, mitophagy, aggrephagy, and tumor suppression."
    explanation: >
      Review confirming mitophagy as one of the selective-autophagy functions
      of optineurin. Evidence source is OTHER because this is a review.
  notes: >
    The mitophagy work cited here is mechanistic cell biology in gene-edited
    non-neuronal lines, not a demonstration in OPTN-mutant human retina. The
    node is curated because the initiation route is TBK1-dependent and so is
    mechanistically continuous with the trigger lesion, but the strength of
    the claim should not be read as equal to the autophagic-flux node above.
  downstream:
  - target: Retinal Ganglion Cell Apoptosis
    causal_link_type: DIRECT
    description: >
      Accumulation of damaged mitochondria in an energetically demanding
      neuron with long unmyelinated intraretinal axons contributes to its
      death.
    evidence:
    - reference: PMID:29951055
      reference_title: "Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Glaucoma-associated mutants of OPTN, E50K, and M98K, cause defective vesicle trafficking, autophagy, and signaling that contribute to death of retinal ganglion cells (RGCs)."
      explanation: >
        Graded PARTIAL: the review supports autophagy-family defects
        contributing to ganglion cell death but does not isolate the mitophagy
        arm specifically, which is why this node is curated as an amplifier.
        Evidence source is OTHER because this is a review.
- name: Disrupted Rab8-Dependent Vesicle Trafficking
  biological_scale: CELLULAR
  role: modifier
  description: >
    Beyond autophagy, optineurin acts as an effector and adaptor for the Rab8
    GTPase, coupling Rab8 to myosin VI and to its GTPase-activating protein
    TBC1D17 to control Golgi-to-plasma-membrane vesicle transport and
    transferrin receptor recycling. The E50K substitution disrupts the
    Optn-Rab8 interaction. This trafficking arm is curated as a modifier
    rather than a second central effector: it is well demonstrated
    biochemically and in transgenic mouse retina, but the pathway from
    disturbed vesicle transport to ganglion cell death is less directly
    evidenced than the autophagic route.
  cell_types:
  - preferred_term: Retinal Ganglion Cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  biological_processes:
  - preferred_term: Intracellular Protein Transport
    term:
      id: GO:0006886
      label: intracellular protein transport
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:20388642
    reference_title: "Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane."
    explanation: >
      Directly demonstrates loss of the Optn-Rab8 interaction as a consequence
      of E50K, in the transgenic mouse study that first reported it.
  - reference: PMID:29951055
    reference_title: "Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Glaucoma-associated mutants of OPTN, E50K, and M98K, cause defective vesicle trafficking, autophagy, and signaling that contribute to death of retinal ganglion cells (RGCs)."
    explanation: >
      Review placing defective vesicle trafficking alongside autophagy as a
      contributor to retinal ganglion cell death. Evidence source is OTHER
      because this is a review article.
  downstream:
  - target: Retinal Ganglion Cell Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Trafficking failure is reported as a contributor to ganglion cell death,
      but the intermediate steps between disturbed vesicle transport and
      apoptosis are not established, hence an indirect edge.
    evidence:
    - reference: PMID:29951055
      reference_title: "Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "Glaucoma-associated mutants of OPTN, E50K, and M98K, cause defective vesicle trafficking, autophagy, and signaling that contribute to death of retinal ganglion cells (RGCs)."
      explanation: >
        Graded INDIRECT: the review bundles trafficking with autophagy and
        signalling as joint contributors and does not establish an
        independent trafficking-to-apoptosis route. Evidence source is OTHER
        because this is a review.
- name: Retinal Ganglion Cell Apoptosis
  conforms_to: "glaucoma_optic_neuropathy#Retinal Ganglion Cell Apoptosis"
  biological_scale: CELLULAR
  role: central_effector
  description: >
    Retinal ganglion cells carrying mutant optineurin die by apoptosis. This is
    the node at which OPTN-related disease rejoins the conserved glaucomatous
    neurodegeneration captured by the `glaucoma_optic_neuropathy` module - but
    it is reached from a cell-autonomous proteostatic lesion rather than from
    the module's trabecular-outflow and elevated-IOP arm, which does not apply
    to this entity. E50K knock-in mice show reduced numbers of viable ganglion
    cells and raised cleaved caspase-3 in the retina at intraocular pressures
    indistinguishable from wild type, and E50K-overexpressing retinal cells
    show an increased early apoptotic fraction.
  cell_types:
  - preferred_term: Retinal Ganglion Cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  biological_processes:
  - preferred_term: Neuron Apoptotic Process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: Retina
    term:
      id: UBERON:0000966
      label: retina
  evidence:
  - reference: PMID:26302410
    reference_title: "Defects in autophagy caused by glaucoma-associated mutations in optineurin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A glaucoma-associated mutant of optineurin, E50K, impairs autophagy as well as vesicle trafficking, leading to death of retinal cells by apoptosis."
    explanation: >
      Connects the upstream autophagy and trafficking lesions to apoptotic
      retinal cell death, which is the claim this node makes.
  - reference: PMID:33723228
    reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of RGCs decreased retinal thickness and visual impairment were observed in OPTN (E50K) mice compared with WT mice."
    explanation: >
      In vivo ganglion cell loss in an E50K knock-in mouse, the animal
      counterpart of this node.
  - reference: PMID:33723228
    reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, overexpression of E50K OPTN induced R28 cell apoptosis."
    explanation: >
      Cell-based confirmation that mutant optineurin is sufficient to induce
      apoptosis in a retinal precursor line.
  - reference: PMID:29951055
    reference_title: "Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Transgenic mice expressing E50K-OPTN show loss of RGCs and persistent reactive gliosis."
    explanation: >
      Review corroborating ganglion cell loss with reactive gliosis in E50K
      transgenic mice. Evidence source is OTHER because this is a review.
  downstream:
  - target: Progressive Glaucomatous Optic Neuropathy at Normal Intraocular Pressure
    causal_link_type: DIRECT
    description: >
      Cumulative ganglion cell and axon loss is what produces the cupping,
      nerve fibre layer thinning and field loss that define the clinical
      entity.
    evidence:
    - reference: PMID:20388642
      reference_title: "Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "After 16 months, histological abnormalities were exclusively observed in the retina of E50K mutant mice with loss of RGCs and connecting synapses in the peripheral retina leading to a thinning of the nerve fiber layer at the optic nerve head at normal IOP."
      explanation: >
        Explicitly links ganglion cell loss to nerve fibre layer thinning at
        the optic nerve head, the structural endpoint of this edge, and does
        so at normal intraocular pressure.
- name: Progressive Glaucomatous Optic Neuropathy at Normal Intraocular Pressure
  conforms_to: "glaucoma_optic_neuropathy#Progressive Glaucomatous Optic Neuropathy"
  biological_scale: ORGANISM
  role: consequence
  description: >
    Cumulative ganglion cell and axon loss produces the clinical entity: deep
    optic disc cupping, retinal nerve fibre layer thinning, and progressive
    visual field loss, with an open and unremarkable drainage angle and
    intraocular pressures at or below 21 mmHg. The defining feature relative to
    the rest of the glaucoma family is that this endpoint is reached without
    the elevated-IOP step: E50K carriers in the Moorfields series had mean
    presenting and peak diurnal IOP of about 15 and 17 mmHg, and E50K mice
    develop retinal degeneration at intraocular pressures statistically
    indistinguishable from wild-type littermates. Relative to mutation-negative
    normal-tension glaucoma the course is more aggressive - younger age at
    presentation, deeper cupping and smaller rim area at diagnosis, and a much
    higher rate of filtration surgery for progressive field loss.
  cell_types:
  - preferred_term: Retinal Ganglion Cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  locations:
  - preferred_term: Optic Nerve
    term:
      id: UBERON:0000941
      label: cranial nerve II
  - preferred_term: Optic Disc
    term:
      id: UBERON:0001783
      label: optic disc
  evidence:
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing."
    explanation: >
      Quantifies the normal intraocular pressures at which the optic
      neuropathy occurs in E50K carriers, which is the defining claim of this
      node.
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields."
    explanation: >
      Supports the more aggressive course relative to mutation-negative
      normal-tension glaucoma asserted in this node.
  - reference: PMID:23669351
    reference_title: "Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The optineurin (OPTN) E50K mutation was first identified in familial primary open-angle glaucoma (POAG), the onset of which is not associated with intraocular pressure (IOP) elevation, and is classified as normal-tension glaucoma (NTG)."
    explanation: >
      States the IOP-independence of onset that separates this node from the
      module's elevated-IOP arm.
  - reference: PMID:37353142
    reference_title: "Familial normal tension glaucoma genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common features of OPTN -associated NTG due to Glu50Lys mutation included early onset of disease with an IOP <21 mm Hg, marked optic disc cupping, and progressive visual field loss"
    explanation: >
      Independent long-follow-up pedigree series describing the same clinical
      triad of early onset, sub-21 mmHg IOP, marked cupping and progressive
      field loss.
  notes: >
    This node deliberately does NOT declare conformance to
    `glaucoma_optic_neuropathy#Elevated Intraocular Pressure` or to the
    module's Trabecular Meshwork Outflow Dysfunction trigger. The module's own
    notes flag normal-tension glaucoma as the partial exception in which
    ganglion cell loss occurs at statistically normal IOP, and this entity is
    that exception.
phenotypes:
- name: Open Angle Glaucoma
  category: Ophthalmological
  diagnostic: true
  description: >
    Glaucomatous optic neuropathy with an open, gonioscopically normal drainage
    angle, arising in adulthood.
  phenotype_term:
    preferred_term: Open angle glaucoma
    term:
      id: HP:0012108
      label: Open angle glaucoma
    onset:
      onset_category: ADULT
      mean_age_years: 40.8
      notes: >
        Adult onset, but at the young end of the adult range: mean age at
        presentation 40.8 years (SD 15) in the Moorfields E50K series,
        significantly younger than mutation-negative normal-tension glaucoma
        controls. Still adult-onset, which distinguishes this entity from
        juvenile open-angle glaucoma.
  evidence:
  - reference: PMID:11834836
    reference_title: "Adult-onset primary open-angle glaucoma caused by mutations in optineurin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a study of 54 families with autosomal dominantly inherited adult-onset POAG, we identified the causative gene on chromosome 10p14 and designated it OPTN (for \"optineurin\")."
    explanation: >
      The gene was identified in families with adult-onset primary open-angle
      glaucoma, establishing the open-angle phenotype for this entity.
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area"
    explanation: >
      Supports the age-at-presentation figure recorded on the onset descriptor
      and its significant difference from mutation-negative NTG controls.
- name: Normal Intraocular Pressure at Presentation
  category: Ophthalmological
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    Unlike most open-angle glaucoma, OPTN-related disease characteristically
    presents with intraocular pressure inside the statistically normal range
    (21 mmHg or less) - the normal-tension glaucoma presentation. All 11
    E50K-carrying patients in the best-characterized clinical series had normal
    tension glaucoma. Because there is no HPO term for normal-tension glaucoma
    and the relevant clinical observation is the ABSENCE of ocular
    hypertension, no `phenotype_term` is bound here rather than binding an
    inapt one; the finding is carried by the description and its evidence.
  evidence:
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing."
    explanation: >
      Reports that all E50K carriers in the series had normal-tension glaucoma
      with quantified normal presenting and peak diurnal pressures, supporting
      the VERY_FREQUENT band in this cohort.
- name: Increased Cup-to-Disc Ratio
  category: Ophthalmological
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    Marked optic disc cupping, deeper at diagnosis than in mutation-negative
    normal-tension glaucoma (mean cup-disc ratio 0.86 in the E50K series, with
    correspondingly smaller neuroretinal rim area).
  phenotype_term:
    preferred_term: Increased cup-to-disc ratio
    term:
      id: HP:0012796
      label: Increased cup-to-disc ratio
  evidence:
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area"
    explanation: >
      Quantifies the cupping in E50K carriers and its significant excess over
      mutation-negative NTG controls, supporting both the phenotype and the
      VERY_FREQUENT band.
  - reference: PMID:37353142
    reference_title: "Familial normal tension glaucoma genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common features of OPTN -associated NTG due to Glu50Lys mutation included early onset of disease with an IOP <21 mm Hg, marked optic disc cupping, and progressive visual field loss"
    explanation: >
      Independent pedigree series listing marked optic disc cupping among the
      common features of Glu50Lys disease.
- name: Glaucomatous Visual Field Defect
  category: Ophthalmological
  frequency: VERY_FREQUENT
  description: >
    Progressive glaucomatous visual field loss. In the Moorfields series every
    E50K-carrying patient had progressing fields, and progression appeared to
    stabilize in a separate long-follow-up pedigree only once intraocular
    pressure was brought below 10 mmHg.
  phenotype_term:
    preferred_term: Glaucomatous visual field defect
    term:
      id: HP:0007854
      label: Glaucomatous visual field defect
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields."
    explanation: >
      All E50K subjects had progressing visual fields, supporting both the
      VERY_FREQUENT band and the PROGRESSIVE course.
  - reference: PMID:37353142
    reference_title: "Familial normal tension glaucoma genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive visual field loss which appeared to stabilize once an IOP of less than 10 mm Hg was achieved"
    explanation: >
      Supports the progressive course and the observation about stabilization
      at very low intraocular pressure quoted in the description.
- name: Abnormal Retinal Nerve Fiber Layer Morphology
  category: Ophthalmological
  description: >
    Thinning of the retinal nerve fibre layer follows ganglion cell axon loss.
    Directly demonstrated in E50K mouse retina, where nerve fibre layer
    thinning at the optic nerve head occurs at normal intraocular pressure;
    this phenotype is therefore supported here by model-organism evidence and
    is annotated without a frequency band.
  phenotype_term:
    preferred_term: Abnormal retinal nerve fiber layer morphology
    term:
      id: HP:0020119
      label: Abnormal retinal nerve fiber layer morphology
  evidence:
  - reference: PMID:20388642
    reference_title: "Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "After 16 months, histological abnormalities were exclusively observed in the retina of E50K mutant mice with loss of RGCs and connecting synapses in the peripheral retina leading to a thinning of the nerve fiber layer at the optic nerve head at normal IOP."
    explanation: >
      Demonstrates nerve fibre layer thinning at normal IOP in the E50K mouse.
      Graded PARTIAL because this is model-organism evidence standing in for a
      human phenotype claim.
genetic:
- name: OPTN
  gene_term:
    preferred_term: OPTN
    term:
      id: hgnc:17142
      label: OPTN
  association: Causative
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:11834836
      reference_title: "Adult-onset primary open-angle glaucoma caused by mutations in optineurin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a study of 54 families with autosomal dominantly inherited adult-onset POAG, we identified the causative gene on chromosome 10p14 and designated it OPTN (for \"optineurin\")."
      explanation: >
        OPTN was identified as causative in autosomal dominantly inherited
        pedigrees.
  variants:
  - name: OPTN p.Glu50Lys (E50K)
    description: >
      The recurrent missense allele of OPTN in normal-tension glaucoma, and
      the most common glaucoma-associated OPTN mutation. Acts by toxic gain of
      function: it strengthens the OPTN-TBK1 interaction, renders optineurin
      insoluble and covalently cross-linked, and blocks autophagic flux.
    gene:
      preferred_term: OPTN
      term:
        id: hgnc:17142
        label: OPTN
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:24983867
      reference_title: "Oligomerization of optineurin and its oxidative stress- or E50K mutation-driven covalent cross-linking: possible relationship with glaucoma pathology."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In cells expressing OPTN bearing the most common glaucoma-associated mutation, E50K, covalent oligomers were formed even without H2O2 stimulation."
      explanation: >
        Identifies E50K as the most common glaucoma-associated OPTN mutation
        and characterizes its biophysical consequence.
    - reference: PMID:27693724
      reference_title: "Significance of optineurin mutations in glaucoma and other diseases."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "we focus on the OPTN E50K mutation, the most common mutation for NTG"
      explanation: >
        Independent review confirming E50K as the most common OPTN mutation in
        normal-tension glaucoma. Evidence source is OTHER because this is a
        review article.
  evidence:
  - reference: PMID:11834836
    reference_title: "Adult-onset primary open-angle glaucoma caused by mutations in optineurin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence alterations in OPTN were found in 16.7% of families with hereditary POAG, including individuals with normal intraocular pressure."
    explanation: >
      Establishes OPTN sequence alterations as the cause in a defined fraction
      of hereditary POAG families, including normal-pressure cases.
  - reference: PMID:11834836
    reference_title: "Adult-onset primary open-angle glaucoma caused by mutations in optineurin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Optineurin is expressed in trabecular meshwork, nonpigmented ciliary epithelium, retina, and brain, and we speculate that it plays a neuroprotective role."
    explanation: >
      Documents the retinal expression that makes a ganglion-cell-autonomous
      mechanism plausible, and the originally proposed neuroprotective role.
  - reference: PMID:29951055
    reference_title: "Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Glaucoma-associated mutations of OPTN are mostly missense mutations."
    explanation: >
      Supports the statement that the glaucoma-causing OPTN allele class is
      predominantly missense. Evidence source is OTHER because this is a
      review article.
  variant_origin: GERMLINE
  notes: >
    OPTN (optineurin) at the GLC1E locus on 10p14 is the causative gene for
    this entity. Glaucoma-associated OPTN changes are predominantly missense;
    the recurrent p.Glu50Lys (E50K) allele segregates with disease in large
    pedigrees and accounts for essentially all of the well-characterized
    mechanistic work. It is a heterozygous germline change acting by toxic
    gain of function rather than by haploinsufficiency - the mutant protein
    acquires abnormal TBK1 binding, insolubility and covalent cross-linking
    rather than merely losing wild-type activity - which is consistent with
    the dominant inheritance. Optineurin is expressed in retina as well as in
    trabecular meshwork and nonpigmented ciliary epithelium, but the
    disease-relevant lesion in this entity is the retinal one.

    The related Mendelian normal-tension glaucoma gene TBK1 is not curated as a
    gene of this entity. TBK1 copy-number gain causes its own normal-tension
    glaucoma and belongs to a separate disease concept; TBK1 appears here only
    as the interacting kinase through which mutant optineurin acts, and as a
    drug target.
- name: OPTN p.Met98Lys (M98K)
  gene_term:
    preferred_term: OPTN
    term:
      id: hgnc:17142
      label: OPTN
  association: Risk Factor
  relationship_type: SUSCEPTIBILITY
  features: >
    M98K is a common OPTN sequence variant repeatedly reported as associated
    with open-angle and normal-tension glaucoma in East Asian cohorts, with
    roughly threefold to fourfold odds ratios in a Japanese case-control
    series, but not replicated in Caucasian populations. It is curated as a
    susceptibility allele, explicitly NOT as a Mendelian cause of this entity:
    the causative-allele evidence in this entry rests on E50K. Mechanistic work
    reports that M98K perturbs autophagy in the opposite direction to E50K -
    enhancing it, with Rab12-dependent transferrin receptor degradation and
    apoptotic retinal cell death - so it is not a milder version of the same
    lesion.
  evidence:
  - reference: PMID:15226658
    reference_title: "Molecular genetic analysis of optineurin gene for primary open-angle and normal tension glaucoma in the Japanese population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of the missense Met98Lys variant was higher in the POAG and NTG groups than in the control group (16.9% versus 5%, 15.4% versus 5%; P = 0.009 and P = 0.029, and odds ratio 3.85 and 3.45, respectively, for the dominant effect of the OPTN A allele)."
    explanation: >
      Quantifies the association of M98K with POAG and NTG in a Japanese
      case-control series, supporting the SUSCEPTIBILITY typing.
  - reference: PMID:26302410
    reference_title: "Defects in autophagy caused by glaucoma-associated mutations in optineurin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A polymorphism of optineurin, M98K, associated with glaucoma, causes enhanced autophagy leading to transferrin receptor degradation and apoptotic death of retinal cells."
    explanation: >
      Supports the claim that M98K acts through enhanced rather than impaired
      autophagy, the opposite direction to E50K.
  notes: >
    The population-specificity of this association cuts both ways and is
    recorded as an open discussion below: the Caucasian-derived causative
    alleles were themselves absent from Japanese glaucoma cohorts.
mechanistic_hypotheses:
- hypothesis_group_id: autophagy_block_model
  hypothesis_label: Autophagic-lysosomal flux block as the primary lesion
  status: CANONICAL
  description: >
    The dominant model: mutant optineurin blocks autophagic flux in retinal
    ganglion cells, undegraded cargo accumulates, and the cells die by
    apoptosis. Supported by concordant LC3-II/p62 accumulation in knock-in
    mice, in E50K-expressing retinal cells, and in isogenic human stem
    cell-derived retinal ganglion cells, and by rescue on pharmacological
    induction of autophagy.
  evidence:
  - reference: PMID:31238079
    reference_title: "Mendelian genes in primary open angle glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in OPTN and TBK1 cause a dysregulation of autophagy which may directly cause retinal ganglion cell damage and normal tension glaucoma."
    explanation: >
      States the autophagy-dysregulation model as the accepted explanation for
      OPTN-related normal-tension glaucoma.
  - reference: PMID:39425218
    reference_title: "Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN(E50K) RGCs"
    explanation: >
      The rescue-on-induction result that upgrades this from an association to
      a causal model.
- hypothesis_group_id: vesicle_trafficking_model
  hypothesis_label: Rab8-dependent vesicle trafficking failure as a parallel lesion
  status: ALTERNATIVE
  description: >
    An alternative or contributory model in which the disease-relevant
    consequence of E50K is loss of the optineurin-Rab8 interaction and the
    consequent failure of Golgi-to-membrane vesicle transport and receptor
    recycling, with autophagic changes secondary. Demonstrated biochemically
    and in transgenic mouse retina, but without an equivalent rescue
    experiment tying it to ganglion cell survival.
  evidence:
  - reference: PMID:20388642
    reference_title: "Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane."
    explanation: >
      Graded PARTIAL: establishes the trafficking lesion this model rests on,
      but does not by itself show that trafficking failure rather than the
      accompanying autophagy defect causes ganglion cell death.
treatments:
- name: Intraocular Pressure Lowering
  description: >
    All established glaucoma therapy works by lowering intraocular pressure,
    and that remains the only evidence-based intervention for OPTN-related
    disease even though the pressure is not elevated to begin with. In a
    four-generation Glu50Lys pedigree followed for a mean of 17 years, visual
    field progression appeared to stabilize only once IOP was brought below
    10 mmHg, so the target pressure is substantially lower than in ordinary
    open-angle glaucoma. This is an observational pedigree finding, not a
    randomized result.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prostaglandin analogue
      term:
        id: NCIT:C78568
        label: Prostaglandin Analogue
    - preferred_term: betaxolol
      term:
        id: CHEBI:3082
        label: betaxolol
    - preferred_term: brimonidine
      term:
        id: CHEBI:3175
        label: brimonidine
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:37353142
    reference_title: "Familial normal tension glaucoma genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive visual field loss which appeared to stabilize once an IOP of less than 10 mm Hg was achieved"
    explanation: >
      The observation behind the very low target pressure recommended for
      OPTN-related normal-tension glaucoma.
  - reference: PMID:27413503
    reference_title: "Update on Normal Tension Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Betaxolol, brimonidine, prostaglandin analogues, trabeculectomy (in refractory cases), systemic calcium channel blockers (such as nifedipine) and 24-hour monitoring of blood pressure are considered in the management of NTG."
    explanation: >
      Source for the agent classes bound in therapeutic_agent. Graded PARTIAL
      and tagged OTHER deliberately: this is a narrative review of
      normal-tension glaucoma in general, NOT of OPTN-related disease, so it
      establishes what is used in NTG management and not that any of these
      agents has OPTN-specific evidence. Calcium channel blockers are named in
      the quote but deliberately not bound as agents here - they target the
      vascular-dysregulation model of non-Mendelian NTG, which is not this
      entity's mechanism.
  - reference: PMID:27413503
    reference_title: "Update on Normal Tension Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment is generally aimed to lower IOP by 30% from pre-existing levels to 12-14 mmHg."
    explanation: >
      The general NTG pressure target, for contrast with the sub-10 mmHg
      target the OPTN-specific pedigree evidence above supports. Graded PARTIAL
      because it is a general-NTG figure, not an OPTN-specific one.
  notes: >
    The agents bound here are the standard normal-tension glaucoma
    pharmacotherapy classes, carried because management of this entity follows
    NTG algorithms. None of them has OPTN-specific efficacy evidence, and none
    addresses the autophagy lesion; they lower pressure in an eye whose
    pressure was never high. That is the therapeutic gap the two
    investigational entries below are aimed at.
- name: Filtration Surgery
  description: >
    Filtering surgery for progressive visual field loss is required far more
    often in E50K carriers than in mutation-negative normal-tension glaucoma
    (72.7% versus 25.3% in the Moorfields series). This reflects the aggressive
    natural history rather than a mutation-specific surgical indication.
  treatment_term:
    preferred_term: Surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003)"
    explanation: >
      Quantifies the excess rate of filtration surgery in E50K carriers.
- name: TBK1 Inhibition (Investigational)
  description: >
    Because the E50K lesion works through an abnormally strong OPTN-TBK1
    interaction, inhibiting TBK1 is the mechanistically obvious intervention.
    The TBK1 inhibitor BX795 reverses the aberrant insolubility of the E50K
    protein in cells, and amlexanox has been reported to protect retinal
    ganglion cells in Optn E50K knock-in mice. INVESTIGATIONAL ONLY - this is
    preclinical cell and mouse data with no human trial evidence, and it must
    not be curated or read as established therapy.

    Only amlexanox is bound in therapeutic_agent. BX795 has no CHEBI or NCIT
    term, and it is deliberately NOT stood in for by a broad drug class: what
    matters mechanistically here is TBK1 selectivity, which a class covering
    every kinase inhibitor does not express. BX795's identity is carried by
    this description and by the cited evidence instead.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amlexanox
      term:
        id: NCIT:C47395
        label: Amlexanox
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: OPTN Missense Variant and Optineurin Misfolding
    treatment_effect: INHIBITS
    description: >
      TBK1 inhibition targets the kinase whose enhanced binding to mutant
      optineurin produces the insolubility that initiates this pathway.
    evidence:
    - reference: PMID:23669351
      reference_title: "Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Treatment with a TBK1 inhibitor, BX795, abrogated the aberrant insolubility of the E50K mutant."
      explanation: >
        Shows that inhibiting TBK1 reverses the specific molecular defect
        modeled by the target node.
  evidence:
  - reference: PMID:27693724
    reference_title: "Significance of optineurin mutations in glaucoma and other diseases."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show for the first time that amlexanox protects RGCs in Optn E50K knock-in mice."
    explanation: >
      Reports retinal ganglion cell protection by a TBK1 inhibitor in an E50K
      knock-in mouse - the strongest in vivo support for this approach, and
      still preclinical.
  - reference: PMID:29951055
    reference_title: "Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TBK1 protein kinase, which mediates E50K-OPTN and M98K-OPTN induced cell death, is emerging as a potential drug target."
    explanation: >
      Review identifying TBK1 as an emerging drug target for OPTN-mutant
      glaucoma. Evidence source is OTHER because this is a review article.
- name: Autophagy Induction (Investigational)
  description: >
    If the primary lesion is a block in autophagic flux, forcing flux should
    rescue the cells. Rapamycin reduced TDP-43 aggregation and increased
    ganglion cell number and visual function in OPTN(E50K) mice, and
    mTOR-independent autophagy induction restored neurite outgrowth in isogenic
    OPTN(E50K) human stem cell-derived ganglion cells. INVESTIGATIONAL ONLY -
    preclinical mouse and human-cell data with no clinical trial evidence.
    Note also that the human-cell work found mTORC1 signalling already
    DECREASED in mutant cells, which is an argument against mTOR inhibitors
    specifically and in favour of mTOR-independent inducers.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rapamycin (sirolimus)
      term:
        id: CHEBI:9168
        label: sirolimus
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Impaired Autophagic Flux in Retinal Ganglion Cells
    treatment_effect: ACTIVATES
    description: >
      Pharmacological induction of autophagy is directed at restoring flux
      through the pathway blocked by mutant optineurin.
    evidence:
    - reference: PMID:39425218
      reference_title: "Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN(E50K) RGCs"
      explanation: >
        Direct rescue of the target node's consequences by inducing autophagy
        in human OPTN(E50K) retinal ganglion cells.
  evidence:
  - reference: PMID:33723228
    reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, rapamycin increased the RGC number and visual function of E50K mice."
    explanation: >
      In vivo rescue of ganglion cell number and visual function by an
      autophagy inducer in an E50K mouse.
animal_models:
- name: Optn E50K knock-in mouse (CRISPR/Cas9 point mutation)
  species: Mouse
  genotype: Optn p.Glu50Lys knock-in
  publication: PMID:33723228
  description: >
    A CRISPR/Cas9 point-mutation knock-in mouse carrying the human-equivalent
    E50K change at the endogenous Optn locus - the closest genetic match to the
    human disease among the available models, since it avoids the
    supraphysiological expression of the transgenic lines. It shows retinal
    ganglion cell loss, retinal thinning, reduced visual function and raised
    cleaved caspase-3, together with blocked autophagic flux and cytoplasmic
    TDP-43 accumulation, at intraocular pressures indistinguishable from
    wild-type littermates. Aged animals also develop spinal cord TDP-43
    pathology and motor dysfunction, mirroring the OPTN link to ALS.
  evidence:
  - reference: PMID:33723228
    reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "OPTN (E50K) mutant mice were generated and analysed for genotype and phenotype."
    explanation: >
      Establishes the existence and characterization of the knock-in model
      described here.
  modeled_mechanisms:
  - target: Retinal Ganglion Cell Apoptosis
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >
      Ganglion cell loss with apoptotic markers at normal intraocular
      pressure, from the endogenous mutant allele.
    evidence:
    - reference: PMID:33723228
      reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The glaucoma-associated E50K mutation in optineurin (OPTN) is known to affect autophagy and cause the apoptosis of retinal ganglion cells (RGCs)"
      explanation: >
        Establishes that this model is informative for the ganglion cell
        apoptosis node it is linked to.
    limitations: >
      The reported animals are homozygous for the knock-in change, whereas
      human disease is heterozygous, so gene dosage is not matched. Mouse
      retina lacks a macula and the mouse optic nerve head has no lamina
      cribrosa, so the biomechanical context of human glaucomatous cupping is
      absent.
    readouts:
    - name: Viable retinal ganglion cell count (NeuN immunolabelling)
      target: Retinal Ganglion Cell Apoptosis
      direction: DECREASED
      interpretation: >
        Fewer surviving ganglion cells in mutant retina, the cellular
        correlate of this node.
      evidence:
      - reference: PMID:33723228
        reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Loss of RGCs decreased retinal thickness and visual impairment were observed in OPTN (E50K) mice compared with WT mice."
        explanation: >
          Reports the ganglion cell loss and retinal thinning that this readout
          measures.
  - target: Impaired Autophagic Flux in Retinal Ganglion Cells
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >
      Autophagic flux is blocked in mutant retina, with the LC3-II/p62
      co-accumulation signature and consequent substrate aggregation.
    evidence:
    - reference: PMID:33723228
      reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In this study, we investigated whether the OPTN (E50K) mutation caused TDP-43 aggregation by disrupting autophagy in vivo and in vitro."
      explanation: >
        States that this model was built and used to interrogate the
        autophagy-disruption node it is linked to.
    limitations: >
      TDP-43 is the substrate whose accumulation was measured; it is a
      well-motivated readout given the shared OPTN link to ALS, but it is not
      established that TDP-43 mishandling is the ganglion-cell-relevant
      consequence of the flux block in human disease.
    readouts:
    - name: Retinal p62/SQSTM1 and LC3-II protein levels
      target: Impaired Autophagic Flux in Retinal Ganglion Cells
      direction: INCREASED
      interpretation: >
        Simultaneous accumulation of an autophagy receptor substrate (p62) and
        of lipidated LC3 indicates a block in flux rather than reduced
        autophagosome formation.
      evidence:
      - reference: PMID:33723228
        reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Increased p62/SQSTM1 and LC3-II levels indicated that autophagic flux was inhibited and contributed to TDP-43 aggregation in vivo and in vitro."
        explanation: >
          Reports exactly the two protein measurements and the flux
          interpretation recorded in this readout.
- name: E50K optineurin transgenic mouse (global overexpression)
  species: Mouse
  genotype: Transgenic overexpression of E50K-mutated optineurin
  publication: PMID:20388642
  description: >
    The first optineurin glaucoma mouse: transgenic global overexpression of
    E50K-mutant optineurin, alongside wild-type and other mutant constructs as
    controls. At 16 months, histological abnormalities were confined to the
    retina in the E50K line, with ganglion cell and synapse loss, nerve fibre
    layer thinning at the optic nerve head, and about a 28% reduction in
    retinal thickness - all at normal intraocular pressure. It is also the
    study that first showed E50K disrupts the Optn-Rab8 interaction.
  evidence:
  - reference: PMID:20388642
    reference_title: "Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we describe the phenotypic characteristics of transgenic mice overexpressing wild-type (Wt) or mutated optineurin (Optn)."
    explanation: >
      Establishes the transgenic overexpression design of this model.
  modeled_mechanisms:
  - target: Progressive Glaucomatous Optic Neuropathy at Normal Intraocular Pressure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >
      Reproduces the defining feature - retinal ganglion cell and nerve fibre
      layer loss occurring at normal intraocular pressure - in the correct
      tissue and with a progressive course.
    evidence:
    - reference: PMID:20388642
      reference_title: "Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These data suggest that alternation of the Optn sequence can initiate significant retinal degeneration in mice."
      explanation: >
        The authors' own summary claim for this model. Graded PARTIAL because
        the claim is for retinal degeneration generally rather than for the
        ganglion-cell-selective optic neuropathy this node describes, which is
        exactly the limitation recorded on the link.
    limitations: >
      The phenotype extends to massive apoptosis and degeneration of the
      entire retina with roughly 28% overall retinal thinning, which is a
      panretinal degeneration rather than the ganglion-cell-selective optic
      neuropathy seen in patients. A later study attributes this to the high
      global overexpression of the transgene and reports diffuse loss of
      photoreceptors and non-RGC cells, features not observed in human POAG.
      Selectivity claims should not be drawn from this line.
    readouts:
    - name: Retinal nerve fiber layer thickness at the optic nerve head
      target: Progressive Glaucomatous Optic Neuropathy at Normal Intraocular Pressure
      direction: DECREASED
      interpretation: >
        Structural correlate of ganglion cell axon loss, measured at normal
        intraocular pressure.
      evidence:
      - reference: PMID:20388642
        reference_title: "Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "After 16 months, histological abnormalities were exclusively observed in the retina of E50K mutant mice with loss of RGCs and connecting synapses in the peripheral retina leading to a thinning of the nerve fiber layer at the optic nerve head at normal IOP."
        explanation: >
          Reports the nerve fibre layer thinning at normal IOP that this
          readout measures.
  - target: Disrupted Rab8-Dependent Vesicle Trafficking
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >
      The study in which loss of the Optn-Rab8 interaction was first
      demonstrated as a molecular consequence of E50K.
    evidence:
    - reference: PMID:20388642
      reference_title: "Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane."
      explanation: >
        This is the study that established the trafficking lesion, so it is by
        construction informative for the node it is linked to.
    limitations: >
      The interaction data are biochemical and were obtained under the same
      overexpression conditions that produce the non-physiological retinal
      phenotype, so the quantitative degree of trafficking disruption at
      endogenous expression levels is not established.
- name: BAC E50K optineurin transgenic mouse (near-physiological expression)
  species: Mouse
  genotype: BAC transgenic human optineurin locus carrying E50K
  publication: PMID:25818176
  description: >
    A bacterial artificial chromosome transgenic line carrying the human
    optineurin locus with its own promoter, designed specifically to avoid the
    global overexpression that made the earlier transgenic line degenerate
    panretinally. At 18 months, mutant animals show enhanced axonal
    degeneration and reduced ganglion cell survival over the age-related
    decline seen in non-transgenic controls, with visual evoked potentials
    revealing a specific contrast-sensitivity deficit.
  evidence:
  - reference: PMID:25818176
    reference_title: "Visual impairment in an optineurin mouse model of primary open-angle glaucoma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To gain mechanistic insights, we developed a novel mouse model based on a mutation in human optineurin associated with hereditary, low-pressure POAG."
    explanation: >
      Establishes the model and its design intent as a low-pressure POAG
      model.
  modeled_mechanisms:
  - target: Retinal Ganglion Cell Apoptosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >
      Mutant optineurin expression accelerates ganglion cell and axon loss
      above the age-related baseline at near-physiological expression levels.
    evidence:
    - reference: PMID:25818176
      reference_title: "Visual impairment in an optineurin mouse model of primary open-angle glaucoma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The E50K optineurin transgenic mouse described here exhibited clinical features of POAG and may be useful for mechanistic dissection of POAG and therapeutic development."
      explanation: >
        The authors' own claim for the model's informativeness. Graded PARTIAL
        because "may be useful" is a prospective claim and the observed effect
        is an increment on an age-related decline seen in controls too.
    limitations: >
      The effect is an enhancement of an age-related decline that also occurs
      in controls rather than a discrete disease phenotype, and it is detected
      only at 18 months, so the model has a narrow window and a small dynamic
      range. Human transgene expression sits on an intact mouse Optn
      background, so this is an overexpression-of-mutant rather than a true
      heterozygous knock-in genotype.
    readouts:
    - name: Healthy optic nerve axon and retinal ganglion cell counts
      target: Retinal Ganglion Cell Apoptosis
      direction: DECREASED
      interpretation: >
        Mutant-specific excess loss of axons and ganglion cells over the
        age-matched non-transgenic decline.
      evidence:
      - reference: PMID:25818176
        reference_title: "Visual impairment in an optineurin mouse model of primary open-angle glaucoma."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Although both 18-month-old optineurin and nontransgenic control mice showed an age-related decrease in healthy axons and RGCs, the expression of mutant optineurin enhanced axonal degeneration and decreased RGC survival."
        explanation: >
          Reports both the shared age-related decline and the mutant-specific
          excess that this readout measures.
    - name: Contrast sensitivity by visual evoked potential
      target: Retinal Ganglion Cell Apoptosis
      direction: DECREASED
      interpretation: >
        Functional correlate of ganglion cell loss in this model.
      evidence:
      - reference: PMID:25818176
        reference_title: "Visual impairment in an optineurin mouse model of primary open-angle glaucoma."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mouse visual function was determined using visual evoked potentials, which revealed specific visual impairment in contrast sensitivity."
        explanation: >
          Reports the visual evoked potential contrast-sensitivity deficit that
          this readout measures.
experimental_models:
- name: Isogenic OPTN(E50K) human pluripotent stem cell-derived retinal ganglion cells
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >
    Human pluripotent stem cell lines in isogenic pairs - patient-derived iPSCs
    with the E50K mutation corrected, and an H7 embryonic line with E50K
    introduced by CRISPR/Cas9 - differentiated through retinal organoids into
    purified retinal ganglion cells. Because the comparison is isogenic, the
    phenotype is attributable to the OPTN genotype rather than to line
    background, and because the cells are human ganglion cells it addresses
    the species limitations of the mouse models directly. Mutant cells show
    impaired autophagic-lysosomal degradation, AMPK activation, reduced mTORC1
    signalling and neurodegenerative features; mTOR-independent autophagy
    induction rescues neurite outgrowth.
  evidence:
  - reference: PMID:39425218
    reference_title: "Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we leveraged an isogenic hPSC model with a glaucoma-associated mutation in the Optineurin (OPTN) protein, which plays a prominent role in autophagy"
    explanation: >
      Establishes the isogenic human stem-cell model described here.
  modeled_mechanisms:
  - target: Impaired Autophagic Flux in Retinal Ganglion Cells
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >
      Human retinal ganglion cells with the disease genotype reproduce the
      autophagic-lysosomal degradation block, in an isogenic comparison.
    evidence:
    - reference: PMID:39425218
      reference_title: "Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Taken together, these results highlighted that autophagy disruption resulted in increased autophagic demand which was associated with downregulated signaling through mTORC1, contributing to the degeneration of RGCs."
      explanation: >
        The study's own conclusion that this human model demonstrates the
        autophagy-disruption node it is linked to.
    limitations: >
      hPSC-derived retinal ganglion cells are developmentally immature relative
      to the adult neurons that degenerate in a disease of middle age, and they
      are cultured without the optic nerve head, lamina cribrosa, glia and
      vasculature of the intact eye. The model therefore speaks to the
      cell-autonomous proteostatic lesion, not to the tissue-level
      neuropathy.
    readouts:
    - name: Autophagic-lysosomal degradation and mTORC1 signalling
      target: Impaired Autophagic Flux in Retinal Ganglion Cells
      direction: DECREASED
      interpretation: >
        Reduced degradative flux with concurrent AMPK activation and lowered
        mTORC1 signalling in mutant human ganglion cells.
      evidence:
      - reference: PMID:39425218
        reference_title: "Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor AMPK, along with subsequent neurodegeneration in OPTN(E50K) RGCs differentiated from hPSCs"
        explanation: >
          Reports both measurements recorded in this readout.
    - name: Neurite outgrowth after mTOR-independent autophagy induction
      target: Impaired Autophagic Flux in Retinal Ganglion Cells
      direction: RESTORED
      interpretation: >
        Rescue on forcing flux, which is what makes the flux block causal for
        the degenerative phenotype rather than merely correlated with it.
      evidence:
      - reference: PMID:39425218
        reference_title: "Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN(E50K) RGCs"
        explanation: >
          Reports the rescue that this readout measures.
discussions:
- discussion_id: optn_mouse_overexpression_fidelity
  prompt: >
    Do the optineurin mouse models, which all rely on mutant overexpression or
    homozygosity, faithfully represent a heterozygous human missense disease
    that spares the outer retina?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - "pathophysiology#Retinal Ganglion Cell Apoptosis"
  - "pathophysiology#Progressive Glaucomatous Optic Neuropathy at Normal Intraocular Pressure"
  rationale: >
    Human OPTN-related glaucoma is a heterozygous, ganglion-cell-selective optic
    neuropathy. None of the three mouse models matches that genotype-phenotype
    pairing. The original transgenic line overexpresses mutant optineurin
    globally and degenerates panretinally, losing photoreceptors and non-RGC
    cells - features explicitly noted as not observed in human POAG. The BAC
    line was built to fix that, and does express near-physiologically, but its
    phenotype is an enhancement of an age-related decline detectable only at 18
    months and still rests on a human transgene over an intact mouse Optn
    background. The knock-in line has the right allele at the right locus but
    is reported as homozygous. Mouse retina additionally has no macula and the
    mouse optic nerve head no lamina cribrosa, removing the biomechanical
    setting in which human glaucomatous cupping develops. The consequence is
    concrete: neuroprotection results and phenotype-selectivity claims from
    these lines should not be transferred to patients without independent
    corroboration.
  evidence:
  - reference: PMID:25818176
    reference_title: "Visual impairment in an optineurin mouse model of primary open-angle glaucoma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This mouse improves the design and phenotype of currently available optineurin mice, which showed high global overexpression."
    explanation: >
      The authors of the BAC line state explicitly that the pre-existing
      optineurin mice suffered from high global overexpression and needed
      improvement, which is the design mismatch this discussion is about.
  - reference: PMID:20388642
    reference_title: "Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "E50K mice also showed massive apoptosis and degeneration of entire retina, leading to approximately a 28% reduction of the retina thickness."
    explanation: >
      Quantifies the panretinal degeneration produced by the overexpression
      model - a whole-retina phenotype rather than the ganglion-cell-selective
      optic neuropathy of the human disease.
  proposed_experiments:
  - experiment_id: optn_heterozygous_knockin_comparison
    name: Heterozygous knock-in comparison
    description: >
      Characterize heterozygous Optn E50K knock-in mice alongside homozygotes
      for ganglion cell survival, autophagic flux and outer retinal integrity,
      to establish whether the ganglion-cell selectivity of human disease is a
      dosage effect.
  - experiment_id: optn_human_retina_validation
    name: Human retinal organoid and post-mortem tissue validation
    description: >
      Test whether the autophagic-flux block and any outer-retinal involvement
      seen in mice are present in OPTN(E50K) human retinal organoids and in
      post-mortem retina from genotyped patients.
- discussion_id: optn_allele_population_specificity
  prompt: >
    Why do the causative and susceptibility OPTN alleles differ so sharply
    between populations, and what does that imply for genetic testing?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#OPTN Missense Variant and Optineurin Misfolding"
  rationale: >
    The OPTN alleles reported as risk-conferring or disease-causing in
    Caucasian cohorts were not detected in Japanese glaucoma patients, while
    M98K shows a robust association with POAG and NTG in Japanese and other
    East Asian series and is not replicated in Caucasians. Normal-tension
    glaucoma is itself more prevalent in East Asian populations. Whether this
    reflects genuinely different allelic architecture, differing linkage
    disequilibrium around a shared functional variant, or ascertainment
    differences between cohorts is unresolved, and it directly affects how an
    OPTN result should be interpreted in a given patient.
  evidence:
  - reference: PMID:14755458
    reference_title: "Mutations in the optineurin gene in Japanese patients with primary open-angle glaucoma and normal tension glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The current results suggest that there may be certain racial differences between Japanese and Caucasians with respect to OPTN genotypes."
    explanation: >
      The primary observation of population-differing OPTN genotypes that this
      discussion is about.
  proposed_experiments:
  - experiment_id: optn_cross_ancestry_sequencing
    name: Cross-ancestry OPTN sequencing with matched phenotyping
    description: >
      Sequence OPTN in large, uniformly phenotyped normal-tension glaucoma
      cohorts across ancestries with shared IOP and disc-imaging protocols, to
      separate allelic architecture from ascertainment.
- discussion_id: optn_glaucoma_als_convergence
  prompt: >
    Do OPTN-related glaucoma and OPTN-related ALS share one pathological
    mechanism differing only in the neuron affected, or are they distinct
    diseases that happen to involve the same gene?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Impaired Autophagic Flux in Retinal Ganglion Cells"
  rationale: >
    OPTN mutations cause both normal-tension glaucoma and ALS, and TBK1 lesions
    likewise cause both. In general the glaucoma-associated alleles are
    missense and the ALS-associated alleles include deletions and nonsense
    changes, with essentially no overlap - which argues for distinct molecular
    consequences. Against that, aged Optn E50K knock-in mice develop spinal
    cord TDP-43 accumulation and motor dysfunction as well as retinal disease,
    and TDP-43 mishandling is the canonical ALS lesion. Resolving this matters
    for whether therapeutic results should be expected to transfer between the
    two diseases.
  evidence:
  - reference: PMID:29875767
    reference_title: "Dysfunction of Optineurin in Amyotrophic Lateral Sclerosis and Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Interestingly, mutations in OPTN, encoding optineurin, are associated with both ALS and glaucoma."
    explanation: >
      Establishes the shared-gene fact that makes this question worth asking.
      Evidence source is OTHER because this is a review article.
  - reference: PMID:29951055
    reference_title: "Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Glaucoma-associated mutations of OPTN are mostly missense mutations."
    explanation: >
      Graded PARTIAL: supports the allele-class asymmetry argued in the
      rationale (glaucoma alleles are predominantly missense) but does not by
      itself state the ALS allele spectrum. Evidence source is OTHER because
      this is a review article.
  - reference: PMID:33723228
    reference_title: "The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In addition, we also observed increased cytoplasmic TDP-43 in the spinal cord and motor dysfunction in 24-month-old OPTN (E50K) mice, indicating that TDP-43 accumulation may be the common pathological mechanism of glaucoma and amyotrophic lateral sclerosis (ALS)."
    explanation: >
      The counter-observation: a glaucoma allele producing ALS-like spinal
      pathology in aged mice, which is the argument for shared mechanism.
diagnosis:
- name: Glaucoma Workup with Documented Normal Intraocular Pressure
  description: >
    The diagnosis is made the same way normal-tension glaucoma is: demonstrate
    a genuinely glaucomatous optic neuropathy, demonstrate an open anterior
    chamber angle, and demonstrate that intraocular pressure stays below
    21 mmHg. Goldmann applanation tonometry (with diurnal assessment where
    peaks are suspected), gonioscopy, slit lamp biomicroscopy, optical
    coherence tomography of the peripapillary nerve fibre layer, and standard
    automated perimetry are the core investigations. Pachymetry matters because
    a thin cornea causes tonometry to underestimate the true pressure and so
    can manufacture an apparent normal-tension case.
  diagnosis_term:
    preferred_term: Tonometry
    term:
      id: NCIT:C120543
      label: Tonometry
  evidence:
  - reference: PMID:27413503
    reference_title: "Update on Normal Tension Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Goldmann applanation tonometry, gonioscopy, slit lamp biomicroscopy, optical coherence tomography and visual field analysis are the main tools of investigation for the diagnosis of NTG."
    explanation: >
      Names the diagnostic battery this entry records. Evidence source is
      OTHER because this is a narrative review.
  - reference: PMID:27413503
    reference_title: "Update on Normal Tension Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Normal tension glaucoma (NTG) is labelled when typical glaucomatous disc changes, visual field defects and open anterior chamber angles are associated with intraocular pressure (IOP) constantly below 21 mmHg."
    explanation: >
      Gives the three diagnostic criteria - disc changes, field defects, open
      angle - together with the sub-21 mmHg pressure requirement. Evidence
      source is OTHER because this is a narrative review.
- name: Gonioscopy
  description: >
    Gonioscopy establishes that the drainage angle is open, which is what
    separates this entity and the rest of the open-angle group from
    angle-closure glaucoma.
  diagnosis_term:
    preferred_term: Gonioscopy
    term:
      id: NCIT:C93195
      label: Gonioscopy
  evidence:
  - reference: PMID:27413503
    reference_title: "Update on Normal Tension Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "open anterior chamber angles on gonioscopy and maximum intraocular pressure (IOP) below 21 mmHg"
    explanation: >
      Establishes gonioscopic confirmation of an open angle as part of the
      diagnostic definition. Evidence source is OTHER because this is a
      narrative review.
- name: Optical Coherence Tomography of the Retinal Nerve Fiber Layer
  description: >
    OCT quantifies peripapillary retinal nerve fibre layer and macular
    ganglion cell complex thickness, and is the structural measure by which
    progression is tracked. It is the clinical readout closest to the
    pathophysiology curated here, since it measures ganglion cell axon loss
    directly.
  diagnosis_term:
    preferred_term: Optical coherence tomography
    term:
      id: NCIT:C20828
      label: Optical Coherence Tomography
  evidence:
  - reference: PMID:27413503
    reference_title: "Update on Normal Tension Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive retinal nerve fiber layer thinning, characteristic visual field defects, open anterior chamber angles on gonioscopy"
    explanation: >
      Identifies progressive nerve fibre layer thinning as a defining,
      trackable feature. Evidence source is OTHER because this is a narrative
      review.
- name: OPTN Genetic Testing
  description: >
    Molecular confirmation. A multigene glaucoma panel is generally preferred
    over isolated OPTN sequencing when the familial variant is unknown, because
    familial normal-tension glaucoma is genetically heterogeneous and TBK1
    copy-number gain - which single-gene sequencing will miss - is a
    differential cause. Where a pathogenic familial variant is already known,
    targeted testing of that variant supports cascade screening of relatives,
    who then need lifelong ophthalmic surveillance because penetrance is
    age-dependent.
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:37353142
    reference_title: "Familial normal tension glaucoma genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 2% of NTG cases are caused primarily by mutations in single genes, optineurin (OPTN), TANK binding kinase 1 (TKB1), or myocilin (MYOC)."
    explanation: >
      Establishes the genetic heterogeneity of familial normal-tension
      glaucoma that motivates panel rather than single-gene testing.
  notes: >
    The pre-test probability is low in unselected normal-tension glaucoma
    (~1% for OPTN), so genetic testing is most informative in familial,
    early-onset, or otherwise atypical disease.
differential_diagnoses:
- name: TBK1-related normal tension glaucoma
  description: >
    Clinically indistinguishable normal-tension glaucoma caused by copy-number
    gain at TBK1 rather than by OPTN missense change. It is the closest
    mechanistic neighbour - TBK1 is the kinase through which mutant optineurin
    acts, and both converge on autophagy dysregulation - and it is the reason
    a genetic evaluation should include copy-number analysis rather than OPTN
    sequencing alone.
  distinguishing_features:
  - >
      Distinguished only by genotype: TBK1 duplication on copy-number testing
      versus an OPTN missense variant on sequencing. Note that a
      sequencing-only panel will miss the TBK1 duplication entirely.
  evidence:
  - reference: PMID:37353142
    reference_title: "Familial normal tension glaucoma genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 2% of NTG cases are caused primarily by mutations in single genes, optineurin (OPTN), TANK binding kinase 1 (TKB1), or myocilin (MYOC)."
    explanation: >
      Lists TBK1 alongside OPTN as a single-gene cause of normal-tension
      glaucoma, which is what makes it the primary differential.
- name: Non-Mendelian normal tension glaucoma
  description: >
    The great majority of normal-tension glaucoma has no single-gene cause.
    Vascular and haemodynamic factors dominate the proposed pathogenesis -
    chronic low ocular perfusion, Raynaud phenomenon, migraine, nocturnal
    systemic hypotension, and over-treated systemic hypertension. Because
    single-gene disease accounts for only about 2% of normal-tension glaucoma,
    this is by far the most likely diagnosis in an unselected patient, and it
    is what an OPTN-related diagnosis has to be positively distinguished from.
  distinguishing_features:
  - >
      Absence of a pathogenic OPTN, TBK1 or MYOC variant; typically older age at
      presentation than the E50K mean of about 41 years, less severe cupping at
      diagnosis, and a lower rate of progression to filtration surgery.
      Vasospastic and nocturnal-hypotension features are commonly present.
  evidence:
  - reference: PMID:27413503
    reference_title: "Update on Normal Tension Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Chronic low vascular perfusion, Raynaud's phenomenon, migraine, nocturnal systemic hypotension and over-treated systemic hypertension are the main causes of normal tension glaucoma."
    explanation: >
      Names the non-genetic causal factors that characterize the far more
      common non-Mendelian form. Evidence source is OTHER because this is a
      narrative review.
- name: Primary open angle glaucoma with unrecognized intraocular pressure peaks
  description: >
    Ordinary high-tension open-angle glaucoma can masquerade as
    normal-tension disease when the pressure elevation is intermittent and
    missed by office-hours tonometry, or when a thin cornea causes applanation
    tonometry to underestimate the true pressure. This is a measurement
    artefact rather than a distinct disease, but it is the commonest reason a
    normal-tension label is wrong.
  distinguishing_features:
  - >
      Diurnal or nocturnal tonometry revealing pressure above 21 mmHg;
      pachymetry showing a thin central cornea that has caused underestimation.
      Normal-tension patients also show wider diurnal pressure fluctuation than
      healthy individuals, so a single normal reading settles nothing.
  evidence:
  - reference: PMID:27413503
    reference_title: "Update on Normal Tension Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IOP spikes may occur at night, and thus IOPs measured during office hours may miss nocturnal spikes in many patients."
    explanation: >
      States the measurement failure mode that produces this differential.
      Evidence source is OTHER because this is a narrative review.
- name: Non-glaucomatous optic neuropathy
  description: >
    Compressive, ischaemic, inflammatory, hereditary (e.g. OPA1-related
    dominant optic atrophy) and mitochondrial optic neuropathies can produce
    optic disc changes and visual field loss without glaucoma. This matters
    for an OPTN entry in particular, because a diagnosis reached partly on the
    grounds of "glaucoma at normal pressure" has already given up the
    pressure criterion and rests more heavily on the pattern of disc and field
    change.
  distinguishing_features:
  - >
      Optic disc pallor exceeding cupping, marked dyschromatopsia, field defects
      respecting the vertical meridian, rapid decline, pain, or accompanying
      neurological signs - any of which should prompt neuroimaging and a
      neuro-ophthalmic assessment rather than glaucoma management.
progression:
- phase: Presymptomatic carrier
  notes: >
    Carriers may have entirely normal optic discs and visual fields well into
    adulthood: seven E50K carriers aged 23-58 years in the Moorfields families
    had no signs of glaucoma at the time of study. Penetrance is age-dependent,
    so surveillance rather than reassurance is the correct response to a
    normal examination in a young carrier.
  evidence:
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma."
    explanation: >
      Documents the presymptomatic carrier phase this record describes.
- phase: Established glaucoma at presentation
  notes: >
    Presentation is at a mean of about 41 years with already-advanced
    structural damage - mean cup-disc ratio 0.86 and reduced neuroretinal rim
    area - which is worse than mutation-negative normal-tension glaucoma at
    diagnosis. The disease has therefore usually been running silently for
    some time before it is found.
  evidence:
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area"
    explanation: >
      Quantifies age and structural damage at presentation for this phase.
- phase: Progressive visual field loss
  notes: >
    All E50K patients in the Moorfields series had progressing visual fields,
    and nearly three quarters required filtration surgery for that
    progression. In a separate four-generation pedigree followed for a mean of
    17 years, progression appeared to stabilize once intraocular pressure was
    brought below 10 mmHg - the practical basis for a very low target
    pressure. Ganglion cell loss is irreversible, so treatment preserves
    remaining function rather than recovering lost vision.
  evidence:
  - reference: PMID:16043855
    reference_title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields."
    explanation: >
      Establishes universal progression and the resulting surgical rate in
      this phase.
  - reference: PMID:37353142
    reference_title: "Familial normal tension glaucoma genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive visual field loss which appeared to stabilize once an IOP of less than 10 mm Hg was achieved"
    explanation: >
      Supports the stabilization-at-very-low-pressure observation recorded for
      this phase.
datasets:
- accession: geo:GSE145069
  title: Differential gene expression and pathway analysis by RNA sequencing in human OPTN(E50K) retinal ganglion cells
  description: >
    RNA-seq of human pluripotent stem cell-derived retinal ganglion cells
    carrying the OPTN(E50K) mutation versus isogenic controls. Genotype- and
    cell-type-specific for this entity: the disease allele in the disease cell
    type, in a human system.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 8
  publication: PMID:32531194
  notes: >
    Located by GEO DataSets search on "optineurin E50K" rather than on the
    disease name; accession, title, sample count and organism are GEO's own
    values, retrieved 2026-08-20. Relevance triage: this is one of only two
    accessions found that are specific to the OPTN(E50K) genotype rather than
    to glaucoma generally - a disease-name search returns trabecular meshwork
    and generic POAG datasets that resolve perfectly but are about the wrong
    entity. Carries no evidence block: an evidence item needs an exact quote
    from the cited abstract, and this record's provenance is the repository
    metadata plus its own linked publication.
- accession: geo:GSE173129
  title: Differential gene expression and pathway analysis by RNA sequencing in human OPTN(E50K) astrocytes
  description: >
    RNA-seq of human stem cell-derived astrocytes carrying OPTN(E50K), from the
    study of non-cell-autonomous contributions to ganglion cell degeneration.
    Complements the ganglion-cell dataset above by covering the glial side of
    the same genotype.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 8
  publication: PMID:35714595
  notes: >
    Located by GEO DataSets search on "optineurin E50K"; accession, title,
    sample count and organism are GEO's own values, retrieved 2026-08-20.
    Note that the astrocyte arm is NOT modeled in this entry's pathophysiology,
    which is curated as a cell-autonomous ganglion cell lesion; a
    non-cell-autonomous glial contribution is plausible but not yet curated
    here. Carries no evidence block for the same reason as the record above.
notes: >
  Scope. This entry covers the Mendelian, OPTN-caused entity. Generic adult
  primary open-angle glaucoma - including the trabecular meshwork outflow
  mechanism and IOP-lowering drug classes - lives in `Glaucoma.yaml`, whose
  `genetic:` section already carries an OPTN record; the two should be read
  together. `Juvenile_Open_Angle_Glaucoma.yaml` covers the mechanistically
  distinct MYOC/CYP1B1 juvenile-onset entity. TBK1-related normal-tension
  glaucoma is a separate concept and is not curated here.

  What is deliberately absent. No `biochemical` markers are curated: there is
  no validated biochemical or imaging biomarker specific to OPTN-related
  disease beyond the structural glaucoma measures already captured as
  phenotypes. The two `datasets` records are deliberately
  restricted to accessions specific to the OPTN(E50K) genotype. A disease-name
  search returns many trabecular meshwork and generic POAG datasets that
  resolve perfectly and are about the wrong entity, since the outflow arm is
  precisely what does not apply here; those were excluded on relevance triage,
  not for lack of candidates.
references:
- reference: PMID:11834836
  title: "Adult-onset primary open-angle glaucoma caused by mutations in optineurin."
- reference: PMID:16043855
  title: "Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene."
- reference: PMID:27693724
  title: "Significance of optineurin mutations in glaucoma and other diseases."
- reference: PMID:37353142
  title: "Familial normal tension glaucoma genetics."
- reference: PMID:31238079
  title: "Mendelian genes in primary open angle glaucoma."
- reference: PMID:29875767
  title: "Dysfunction of Optineurin in Amyotrophic Lateral Sclerosis and Glaucoma."
- reference: PMID:27413503
  title: "Update on Normal Tension Glaucoma."

📚

References & Deep Research

References

7

PMID:11834836

Adult-onset primary open-angle glaucoma caused by mutations in optineurin.

No top-level findings curated for this source.

PMID:16043855

Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene.

No top-level findings curated for this source.

PMID:27693724

Significance of optineurin mutations in glaucoma and other diseases.

No top-level findings curated for this source.

PMID:37353142

Familial normal tension glaucoma genetics.

No top-level findings curated for this source.

PMID:31238079

Mendelian genes in primary open angle glaucoma.

No top-level findings curated for this source.

PMID:29875767

Dysfunction of Optineurin in Amyotrophic Lateral Sclerosis and Glaucoma.

No top-level findings curated for this source.

PMID:27413503

Update on Normal Tension Glaucoma.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

OPTN-Related Open-Angle Glaucoma: Disease-Characteristics Research Report

Edison Scientific Literature 46 citations 2026-08-20T14:39:43.305588

OPTN-Related Open-Angle Glaucoma: Disease-Characteristics Research Report

Executive summary

OPTN-related open-angle glaucoma—historically GLC1E—is a rare Mendelian form of open-angle glaucoma caused most convincingly by heterozygous pathogenic variation in OPTN, particularly p.Glu50Lys (E50K). It usually manifests as adult-onset normal-tension glaucoma (NTG): progressive retinal ganglion-cell (RGC) and optic-nerve degeneration, optic-disc cupping, retinal nerve-fiber-layer (RNFL) thinning, and corresponding visual-field loss despite untreated intraocular pressure (IOP) remaining below 21 mmHg. It should be distinguished from common, complex primary open-angle glaucoma (POAG), in which OPTN variants generally explain only a small fraction of disease. (trivli2020primaryopenangle pages 1-2, salvetat2023pharmaceuticalapproachesto pages 1-2, swarup2018alteredfunctionsand pages 1-3)

The evidence hierarchy is important. E50K has family segregation, cellular, animal-model, and human stem-cell evidence. By contrast, M98K is better regarded as a population-dependent susceptibility/modifier allele, and many other reported variants remain insufficiently validated. Current treatment is not genotype-specific: clinicians lower IOP even when it is statistically normal, monitor structural and functional progression, and escalate to laser or surgery when necessary. No approved OPTN-directed therapy or qualifying OPTN-specific interventional clinical trial was identified. (salvetat2023pharmaceuticalapproachesto pages 1-2, swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)

The following table provides a compact ontology-ready summary; the narrative below expands the evidence and identifies gaps.

Domain	Curated statement	Suggested ontology IDs/terms	Evidence type/strength	Key source/date/PMID or DOI
Disease identity	OPTN-related open-angle glaucoma corresponds to the Mendelian glaucoma locus GLC1E and is best regarded as a rare monogenic subset of open-angle glaucoma, often presenting as normal-tension glaucoma (NTG) rather than a separate common POAG entity. OMIM 137760 (GLC1E) is commonly used in the literature; use the broader MONDO:0005338 open-angle glaucoma only as a parent term, with caution because a disease-specific MONDO for OPTN-related glaucoma was not confirmed here.	OMIM:137760 (GLC1E, use with caution if local curation confirms); MONDO:0005338 open-angle glaucoma (broader parent); MeSH/ICD disease mapping not verified in current context	Human genetic literature + review synthesis; moderate strength for GLC1E identity, lower strength for ontology cross-mapping gaps (OpenTargets Search: open-angle glaucoma-OPTN, trivli2020primaryopenangle pages 1-2, swarup2018alteredfunctionsand pages 1-3)	Rezaie et al. discovery paper cited in reviews; Trivli 2020 DOI:10.3892/mmr.2020.11215; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Source type	This knowledge-base entry should be based on aggregated disease-level resources and published case/family studies, not EHR-derived evidence.	ECO conceptually: literature evidence; disease knowledgebase curation	Curatorial statement; high confidence	Review/resource-based synthesis (trivli2020primaryopenangle pages 1-2, milla2024nextgenerationsequencingbasedgene pages 1-2)
Causal gene	OPTN (optineurin) is the causal gene implicated in GLC1E; it lies on chromosome 10p13 and encodes a multifunctional adaptor involved in vesicle trafficking, autophagy, and signaling.	HGNC:17142 OPTN; Ensembl: ENSG00000123240; chromosomal location: 10p13	Strong human genetic and molecular evidence (OpenTargets Search: open-angle glaucoma-OPTN, trivli2020primaryopenangle pages 1-2, swarup2018alteredfunctionsand pages 1-3)	Open Targets context for OPTN–open-angle glaucoma association; Trivli 2020 DOI:10.3892/mmr.2020.11215; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Inheritance	Inheritance is autosomal dominant for the clearest familial OPTN-associated disease, especially E50K; penetrance appears age-dependent and incomplete/incompletely defined. Reviews note segregation of E50K in affected individuals over ~30 years in a large family, while most other alleles have weaker evidence.	HPO inheritance term: HP:0000006 Autosomal dominant inheritance	Human family evidence; moderate for AD, limited for exact penetrance (swarup2018alteredfunctionsand pages 1-3, trivli2020primaryopenangle pages 1-2)	Swarup 2018 DOI:10.3389/fimmu.2018.01287; Trivli 2020 DOI:10.3892/mmr.2020.11215
Variant spectrum	Reported glaucoma-associated OPTN variants are mostly missense. The strongest disease-causing allele is p.Glu50Lys (E50K). Other reported variants include M98K, H26D, H486R, E322K, R545Q and others, but not all have equivalent evidence.	Sequence Ontology: SO:0001583 missense_variant	Human genetic + mechanistic literature; moderate overall, strongest for E50K (swarup2018alteredfunctionsand pages 1-3, rozpedekkaminska2020thegeneticand pages 26-28, venkatesan2025proteinmisfoldingand pages 8-9)	Swarup 2018 DOI:10.3389/fimmu.2018.01287; Rozpędek-Kamińska 2020 DOI:10.3390/ijms21114171; Venkatesan 2025 DOI:10.3389/fcell.2025.1595121
Variant interpretation: E50K	E50K is the best-supported pathogenic OPTN glaucoma allele: dominant family segregation, repeated mechanistic support, and disease-recapitulating mouse/hPSC-RGC models.	HGVS protein: p.Glu50Lys; ClinVar classification not directly verified in current context	Strongest OPTN-specific evidence (human + animal + in vitro) (swarup2018alteredfunctionsand pages 1-3, nagabhushana2010regulationofendocytic pages 1-2, huang2024acquisitionofneurodegenerative pages 1-2)	Nagabhushana 2010 DOI:10.1186/1471-2121-11-4; Huang 2024 DOI:10.1186/s40478-024-01872-2; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Variant interpretation: M98K	M98K is best treated as a disputed or population-dependent risk/modifier allele, not a universally established monogenic pathogenic variant. Association appears stronger in some Asian cohorts and weaker/absent in others.	HGVS protein: p.Met98Lys; classify cautiously as risk allele/uncertain modifier unless lab-specific evidence supports pathogenicity	Mixed human association + mechanistic data; lower certainty than E50K (swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)	Swarup 2018 DOI:10.3389/fimmu.2018.01287; Sirohi 2015 DOI:10.1371/journal.pone.0138289
Variant interpretation: H486R/R545Q/others	H486R, R545Q, E322K and several other alleles have been reported, but the current context does not provide enough evidence for definitive pathogenic classification, penetrance, or population frequency.	Use ACMG/AMP categories only after external verification; likely VUS/uncertain in this context	Limited evidence/data gap (rozpedekkaminska2020thegeneticand pages 26-28, swarup2018alteredfunctionsand pages 1-3)	Rozpędek-Kamińska 2020 DOI:10.3390/ijms21114171; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Epidemiology	OPTN mutations account for only a small minority of POAG/NTG, often cited around ~1% or less of sporadic NTG/POAG, while Mendelian forms overall account for about 5% of POAG. Disease prevalence for the specific OPTN-related entity is not established.	MONDO:0005338 parent disease epidemiology only; no disease-specific ORDO/MONDO confirmed	Human literature; moderate for rarity, low for exact prevalence (trivli2020primaryopenangle pages 1-2, swarup2018alteredfunctionsand pages 1-3)	Trivli 2020 DOI:10.3892/mmr.2020.11215; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Core phenotype	Typical phenotype is adult-onset open-angle glaucomatous optic neuropathy, often normal-tension glaucoma with optic disc cupping, RNFL loss, retinal ganglion cell degeneration, and progressive visual field loss despite IOP in the statistically normal range.	HPO: HP:0000505 Visual field defect; HP:0001138 Increased cup-to-disc ratio; HP:0007773 Optic atrophy; HP:0001103 Visual loss; HP:0000548 Abnormality of the optic nerve; parent glaucoma terms as local ontology allows	Human clinical + guideline/review evidence; strong for general NTG phenotype, moderate for OPTN-specific mapping (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2, swarup2018alteredfunctionsand pages 1-3)	Salvetat 2023 DOI:10.3390/ph16081172; Mallick 2016 DOI:10.4103/2008-322X.183914; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Age of onset/course	Onset is usually adult and disease course is chronic and progressive. E50K familial disease showed age-dependent expression in adults; exact median onset for OPTN-specific disease remains insufficiently quantified here.	HPO: HP:0003581 Adult onset; HP:0003676 Progressive	Human family/review evidence; moderate (swarup2018alteredfunctionsand pages 1-3, salvetat2023pharmaceuticalapproachesto pages 1-2)	Swarup 2018 DOI:10.3389/fimmu.2018.01287; Salvetat 2023 DOI:10.3390/ph16081172
IOP phenotype	A substantial subset of OPTN-related disease presents with IOP consistently <21 mmHg, i.e., NTG; however, some literature places OPTN within the broader POAG spectrum.	HPO suggestion: Normal intraocular pressure phenotype not confirmed in HPO here; clinical descriptor “normal-tension glaucoma”	Human clinical/review evidence; moderate (salvetat2023pharmaceuticalapproachesto pages 1-2, swarup2018alteredfunctionsand pages 1-3)	Salvetat 2023 DOI:10.3390/ph16081172; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Affected anatomy	Primary structures affected: retina, retinal nerve fiber layer, optic nerve head, optic nerve, and likely trabecular meshwork for some pathway interactions, though the major neurodegenerative target is the RGC/optic nerve axis.	UBERON: retina (UBERON:0000966); optic nerve (UBERON:0000978); optic nerve head (UBERON term should be externally verified); trabecular meshwork (UBERON term externally verify)	Human/animal/in vitro evidence; moderate-strong for retina/optic nerve, weaker for TM relevance (huang2024acquisitionofneurodegenerative pages 1-2, tsai2024glaucomaanimalmodels pages 1-2, trivli2020primaryopenangle pages 1-2)	Huang 2024 DOI:10.1186/s40478-024-01872-2; Tsai 2024 DOI:10.3390/ijms25020906; Trivli 2020 DOI:10.3892/mmr.2020.11215
Cell types	Main vulnerable cells are retinal ganglion cells (RGCs); secondary involvement includes astrocytes/glia and possibly trabecular meshwork cells in broader glaucoma biology.	CL:0000740 retinal ganglion cell; CL:0000127 astrocyte; trabecular meshwork cell CL term externally verify	Strong for RGCs, moderate for glia/TM (huang2024acquisitionofneurodegenerative pages 1-2, tsai2024glaucomaanimalmodels pages 1-2, swarup2018alteredfunctionsand pages 1-3)	Huang 2024 DOI:10.1186/s40478-024-01872-2; Tsai 2024 DOI:10.3390/ijms25020906; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Subcellular localization	Relevant subcellular compartments include Golgi/recycling endosomes, autophagosomes/lysosomes, and mitochondria/mitophagy machinery.	GO:0005794 Golgi apparatus; GO:0005768 endosome; GO:0005776 autophagosome; GO:0005764 lysosome; GO:0005739 mitochondrion	Strong mechanistic evidence (nagabhushana2010regulationofendocytic pages 1-2, huang2024acquisitionofneurodegenerative pages 1-2, venkatesan2025proteinmisfoldingand pages 6-7)	Nagabhushana 2010 DOI:10.1186/1471-2121-11-4; Huang 2024 DOI:10.1186/s40478-024-01872-2; Venkatesan 2025 DOI:10.3389/fcell.2025.1595121
Major mechanism: trafficking	OPTN normally regulates endocytic recycling/vesicle trafficking; E50K impairs transferrin receptor trafficking, enlarges recycling endosomes, slows vesicle dynamics, and alters Rab8 interactions.	GO:0006897 endocytosis; GO:0006886 intracellular protein transport; GO:0032456 endocytic recycling; GO:0005515 protein binding; RAB8 pathway annotation as local pathway system allows	In vitro mechanistic evidence; strong (nagabhushana2010regulationofendocytic pages 1-2)	Nagabhushana 2010 DOI:10.1186/1471-2121-11-4
Major mechanism: autophagy/mitophagy	OPTN is an autophagy receptor; glaucoma-associated mutants perturb autophagic flux, cargo sequestration, and mitophagy. TBK1-mediated phosphorylation enhances LC3 binding and selective autophagy functions.	GO:0006914 autophagy; GO:0000422 mitophagy; GO:0005776 autophagosome; GO:0016236 macroautophagy; GO:0000045 autophagosome assembly	Strong review + human cell evidence (venkatesan2025proteinmisfoldingand pages 6-7, huang2024acquisitionofneurodegenerative pages 1-2, swarup2018alteredfunctionsand pages 1-3)	Huang 2024 DOI:10.1186/s40478-024-01872-2; Swarup 2018 DOI:10.3389/fimmu.2018.01287; Venkatesan 2025 DOI:10.3389/fcell.2025.1595121
Major mechanism: TBK1 axis	OPTN interacts with TBK1, a major partner in NTG biology. For E50K and M98K, altered TBK1 coupling/phosphorylation is implicated in autophagy-related retinal cell death.	GO:0006468 protein phosphorylation; GO:0032480 negative regulation of type I interferon production/innate immune pathways as context-dependent; pathway label “OPTN-TBK1 autophagy axis”	Strong mechanistic support; human genetics indirect, cell/animal strong (venkatesan2025proteinmisfoldingand pages 6-7, sirohi2015aglaucomaassociatedvariant pages 1-2, swarup2018alteredfunctionsand pages 1-3)	Sirohi 2015 DOI:10.1371/journal.pone.0138289; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Major mechanism: neurodegeneration	Downstream biology includes RGC neurite retraction, protein accumulation, apoptosis/caspase activation, reactive gliosis, and optic nerve degeneration.	GO:0043524 negative regulation of neuron apoptotic process (or apoptosis terms as appropriate); GO:0097458 neuron part morphogenesis; GO:0006915 apoptotic process; GO:0006954 inflammatory response	Strong in vitro/animal evidence (huang2024acquisitionofneurodegenerative pages 18-20, huang2023elucidatingcellularmechanisms pages 46-51, swarup2018alteredfunctionsand pages 1-3)	Huang 2024 DOI:10.1186/s40478-024-01872-2; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Signaling/metabolic mechanisms	Recent 2024 hPSC-RGC work links OPTN(E50K) to impaired autophagic-lysosomal degradation, AMPK activation, and reduced mTORC1 signaling; mTORC1 inhibition in control RGCs recapitulated disease features, while mTOR-independent autophagy induction was rescuing.	GO:0005773 vacuole/lysosome system; GO:0010506 regulation of autophagy; GO:0032008 positive regulation of TOR signaling / GO:0031929 TORC1 signaling; AMPK pathway terms via Reactome/GO locally	Strong recent human-cell evidence (huang2024acquisitionofneurodegenerative pages 1-2, huang2024acquisitionofneurodegenerative pages 18-20, huang2024acquisitionofneurodegenerative pages 14-16)	Huang 2024 DOI:10.1186/s40478-024-01872-2
Inflammation/immune involvement	Neuroinflammation is increasingly implicated in NTG models; OPTN biology also intersects innate immune signaling. For OPTN(E50K), reactive gliosis and, in later literature, inflammasome activation are suggested, but OPTN-specific human evidence remains limited.	GO:0006954 inflammatory response; GO:0045087 innate immune response; CL astrocyte/microglia terms locally as needed	Moderate, mostly model/review-based (tsai2024glaucomaanimalmodels pages 1-2, swarup2018alteredfunctionsand pages 1-3)	Tsai 2024 DOI:10.3390/ijms25020906; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Risk factors beyond OPTN	General NTG risk factors likely modify disease expression: older age, female sex, family history, vascular dysregulation, Raynaud phenomenon, migraine, nocturnal hypotension, myopia, smoking, systemic hypertension/impaired glucose tolerance, and possibly sleep apnea. These are not OPTN-specific but clinically relevant modifiers.	HPO/ExO environmental annotations as local system allows; HP:0000822 hypertension; HP:0001279 migraine; myopia term if used locally	General NTG/POAG evidence, extrapolated to OPTN carriers with caution (mallick2016updateonnormal pages 1-2, salvetat2023pharmaceuticalapproachesto pages 1-2)	Mallick 2016 DOI:10.4103/2008-322X.183914; Salvetat 2023 DOI:10.3390/ph16081172
Protective factors/data gaps	No well-established OPTN-specific protective genetic variants were identified in the current context. Lifestyle or metabolic neuroprotective strategies are experimental and not validated as preventive measures for OPTN carriers.	Data gap	Low/insufficient evidence	No definitive evidence in current context
Diagnosis	Diagnosis follows standard NTG/POAG workup: Goldmann applanation tonometry, gonioscopy, slit-lamp/fundus examination, OCT/RNFL imaging, and automated perimetry; importantly, clinicians must exclude nonglaucomatous optic neuropathy when cupping occurs with normal IOP.	LOINC/NCIT local mapping: tonometry, gonioscopy, OCT, perimetry; HPO phenotypes above	Strong guideline/review evidence for clinical workup; indirect for OPTN-specific diagnosis (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2)	Salvetat 2023 DOI:10.3390/ph16081172; Mallick 2016 DOI:10.4103/2008-322X.183914
Genetic testing	A practical approach is multigene glaucoma panel testing (including OPTN, MYOC, TBK1, WDR36, CYP1B1 and others) in familial/early-onset/NTG cases; recent NGS panel work supports molecular diagnosis but stresses need for segregation and functional follow-up for rare variants.	HGNC genes for panel: OPTN, MYOC, TBK1, WDR36, CYP1B1; sequence analysis	Human molecular diagnostics evidence; moderate (milla2024nextgenerationsequencingbasedgene pages 1-2, trivli2020primaryopenangle pages 1-2)	Milla 2024 DOI:10.1371/journal.pone.0282133; Trivli 2020 DOI:10.3892/mmr.2020.11215
Differential diagnosis	Differential diagnosis includes other causes of optic nerve cupping/optic neuropathy rather than glaucoma alone, especially in normal-IOP presentations.	HPO optic atrophy spectrum; non-glaucomatous optic neuropathy terms locally	Guideline/review evidence; moderate (salvetat2023pharmaceuticalapproachesto pages 1-2)	Salvetat 2023 DOI:10.3390/ph16081172
Prognosis	Disease is typically progressive and can lead to irreversible visual disability/blindness if untreated. Even with IOP lowering, some NTG patients continue to progress, implying non-IOP mechanisms. OPTN-specific long-term survival/mortality data are unavailable.	HPO: HP:0003676 Progressive; HP:0001103 Visual loss	Strong for progressive visual morbidity; low for OPTN-specific natural history estimates (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2)	Salvetat 2023 DOI:10.3390/ph16081172; Mallick 2016 DOI:10.4103/2008-322X.183914
Quality of life	Visual field loss and optic neuropathy reduce visual function and quality of life; glaucoma models/reviews emphasize impact on independence and psychological burden, but OPTN-specific QoL studies were not identified.	PROM/QoL terms not specifically mapped here	General glaucoma evidence; indirect for OPTN-specific disease (tsai2024glaucomaanimalmodels pages 1-2, salvetat2023pharmaceuticalapproachesto pages 1-2)	Tsai 2024 DOI:10.3390/ijms25020906; Salvetat 2023 DOI:10.3390/ph16081172
Standard treatment	No OPTN-specific approved therapy exists. Management follows NTG/POAG care with IOP lowering as standard of care, even when baseline IOP is normal. Typical medical options include prostaglandin analogs, beta-blockers, alpha-agonists, carbonic anhydrase inhibitors; surgery is used when needed.	NCIT examples: prostaglandin analog therapy; trabeculectomy; laser trabeculoplasty; minimally invasive glaucoma surgery	Strong clinical standard-of-care evidence, indirect for genotype specificity (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2, tsai2024glaucomaanimalmodels pages 1-2)	Salvetat 2023 DOI:10.3390/ph16081172; Mallick 2016 DOI:10.4103/2008-322X.183914; Tsai 2024 DOI:10.3390/ijms25020906
Treatment targets	Reviews commonly cite a target of roughly 30% IOP reduction in NTG management; this is a clinical principle extrapolated to OPTN-related disease, not a genotype-tested threshold.	Clinical management rule; no ontology term needed	General NTG evidence; indirect to OPTN (mallick2016updateonnormal pages 1-2, salvetat2023pharmaceuticalapproachesto pages 1-2)	Mallick 2016 DOI:10.4103/2008-322X.183914; Salvetat 2023 DOI:10.3390/ph16081172
Experimental therapeutics	Preclinical work supports TBK1-axis modulation, autophagy correction, and neuroprotective strategies; in 2024 hPSC-RGCs, trehalose rescued neurite/protein-accumulation phenotypes via mTOR-independent autophagy induction. These remain experimental.	CHEBI: trehalose (local CHEBI mapping can be added); GO autophagy terms above	Strong preclinical, no clinical validation (huang2024acquisitionofneurodegenerative pages 1-2, huang2024acquisitionofneurodegenerative pages 18-20, sirohi2015aglaucomaassociatedvariant pages 1-2)	Huang 2024 DOI:10.1186/s40478-024-01872-2; Sirohi 2015 DOI:10.1371/journal.pone.0138289
Animal models	Key models include OPTN E50K knock-in/transgenic mice, which show RGC loss and reactive gliosis, and are used as NTG-like models beyond IOP elevation.	NCBI Taxon:10090 Mus musculus; phenotype terms: RGC loss, gliosis	Strong model evidence (tsai2024glaucomaanimalmodels pages 1-2, swarup2018alteredfunctionsand pages 1-3)	Tsai 2024 DOI:10.3390/ijms25020906; Swarup 2018 DOI:10.3389/fimmu.2018.01287
Human cellular models	Isogenic hPSC-/iPSC-derived retinal ganglion cells carrying OPTN(E50K) reproduce neurodegenerative phenotypes, autophagy defects, AMPK activation, mTORC1 reduction, protein accumulation, and neurite retraction; useful for mechanistic studies and drug screening.	CL:0000740 retinal ganglion cell; EFO/pluripotent stem cell terms locally	Strong recent human in vitro evidence (huang2024acquisitionofneurodegenerative pages 1-2, huang2024acquisitionofneurodegenerative pages 18-20, huang2024acquisitionofneurodegenerative pages 16-18)	Huang 2024 DOI:10.1186/s40478-024-01872-2
Evidence gaps/curation cautions	Key gaps: no confirmed disease-specific MONDO ID in current context; limited penetrance estimates; uncertain pathogenicity for several non-E50K alleles; sparse allele-frequency data; minimal OPTN-specific prognosis/QoL/prevention data; many management statements are extrapolated from general NTG/POAG rather than genotype-stratified studies.	Curation flag: evidence gap/needs external verification	High-confidence curation caveat	Synthesized from all cited contexts (OpenTargets Search: open-angle glaucoma-OPTN, salvetat2023pharmaceuticalapproachesto pages 1-2, milla2024nextgenerationsequencingbasedgene pages 1-2, swarup2018alteredfunctionsand pages 1-3)

Table: This table summarizes ontology-ready core facts for OPTN-related open-angle glaucoma, separating well-supported evidence such as the E50K/GLC1E association from broader NTG extrapolations and unresolved data gaps. It is designed to support structured disease knowledge-base curation.

1. Disease information

Definition and scope

Glaucoma is a chronic progressive optic neuropathy defined by loss of RGC bodies and axons, RNFL thinning, characteristic optic-nerve-head cupping, and irreversible visual-field defects. NTG is the open-angle subtype in which glaucomatous structural and functional damage occurs without measured untreated IOP elevation. The 2023 Japanese definition cited in a recent review describes NTG as POAG in which IOP remains within the statistically normal range during development of glaucomatous optic neuropathy. (salvetat2023pharmaceuticalapproachesto pages 1-2)

For knowledge-base purposes, OPTN-related open-angle glaucoma should be modeled as a rare genetic child of open-angle glaucoma/NTG, not as synonymous with all NTG. Open Targets records an OPTN–open-angle-glaucoma association for ENSG00000123240 and the broader disease MONDO:0005338, supported by five evidence records and literature including PMID 11834836. (OpenTargets Search: open-angle glaucoma-OPTN)

Identifiers and synonyms

Preferred name: OPTN-related open-angle glaucoma
Common synonyms: glaucoma 1, open-angle, E; GLC1E; optineurin-related glaucoma; OPTN-associated glaucoma; familial normal-tension glaucoma due to OPTN
Gene: OPTN, optineurin; Ensembl ENSG00000123240; chromosome 10p13. (OpenTargets Search: open-angle glaucoma-OPTN, trivli2020primaryopenangle pages 1-2)
OMIM: 137760 is commonly used for GLC1E in secondary disease resources; confirm against the live OMIM record before production ingestion.
MONDO: no disease-specific OPTN child identifier was verified by the available tools; use MONDO:0005338, open-angle glaucoma, as a parent rather than claiming it uniquely denotes OPTN disease. (OpenTargets Search: open-angle glaucoma-OPTN)
ICD-10-CM: typically coded clinically under primary open-angle or low/normal-tension glaucoma, with eye and stage modifiers; there is no OPTN-genotype-specific ICD-10 code.
ICD-11/MeSH/Orphanet: no genotype-specific identifier was verified in the retrieved evidence. Map to open-angle/normal-tension glaucoma and preserve OPTN as the molecular qualifier.

This report is based on aggregated disease-level databases, published families, cohorts, reviews, and experimental models, not individual EHR-derived observations.

Landmark discovery

Rezaie and colleagues reported “Adult-onset primary open-angle glaucoma caused by mutations in optineurin” in Science on 8 February 2002, DOI 10.1126/science.1066901, PMID 11834836. Subsequent synthesis reports OPTN variants in 16.7% of the originally studied linked families, but only about 1% or less of sporadic NTG; thus the original family statistic must not be interpreted as population prevalence. E50K segregated with glaucoma in affected members older than approximately 30 years. (OpenTargets Search: open-angle glaucoma-OPTN, swarup2018alteredfunctionsand pages 1-3)

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

The clearest etiology is a heterozygous germline OPTN variant with dominant toxic or altered-function effects, especially E50K. OPTN is a multifunctional cytoplasmic adaptor involved in Golgi integrity, endosomal trafficking, autophagy/mitophagy, and inflammatory signaling. Disease is principally a neurodegeneration of RGCs and their axons rather than an infectious, neoplastic, or primary metabolic disorder. (venkatesan2025proteinmisfoldingand pages 6-7, trivli2020primaryopenangle pages 1-2, swarup2018alteredfunctionsand pages 1-3)

Genetic risk factors

E50K/p.Glu50Lys: strongest causal evidence; dominant segregation and extensive functional/model support.
M98K/p.Met98Lys: mechanistically active in experimental systems, but human association is stronger in some Asian populations and absent or weak in several Caucasian studies; curate as a risk/modifier allele unless case-level segregation and classification justify otherwise. (swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)
H26D, E322K, H486R, R545Q and other reported missense alleles: evidence is heterogeneous and generally weaker than for E50K. Do not automatically label all as pathogenic. (rozpedekkaminska2020thegeneticand pages 26-28, venkatesan2025proteinmisfoldingand pages 8-9, swarup2018alteredfunctionsand pages 1-3)
Modifier/cognate pathway genes: TBK1 is a strong mechanistic partner and an independent cause of familial NTG through copy-number gain; MYOC, WDR36 and CYP1B1 are relevant differential or panel genes. OPTN overexpression can increase endogenous MYOC in trabecular-meshwork cells, but a reproducible OPTN-specific modifier architecture has not been established. (trivli2020primaryopenangle pages 1-2)

Environmental and systemic modifiers

No exposure is known to create the germline disorder. General NTG/POAG factors may affect penetrance or progression: age, family history, myopia, thin central cornea, vascular dysregulation, migraine, Raynaud phenomenon, nocturnal hypotension, excessive antihypertensive treatment, smoking, metabolic disease, and sleep apnea/hypoxic stress. These data are extrapolated from general NTG, not demonstrated OPTN-specific gene–environment interactions. (trivli2020primaryopenangle pages 1-2, mallick2016updateonnormal pages 1-2)

Mechanistically plausible interactions include oxidative stress, hypoxia/ischemia–reperfusion, and aging increasing autophagic and mitochondrial demand in already vulnerable OPTN-mutant RGCs. However, prospective carrier studies quantifying such interactions are lacking.

Protective factors

No validated OPTN protective allele, diet, supplement, or lifestyle intervention is established. Avoidance of smoking, treatment of sleep apnea, review of excessive nocturnal blood-pressure reduction, and general cardiovascular health are reasonable clinical measures but are not proven to prevent OPTN glaucoma. Experimental autophagy-enhancing or metabolic interventions cannot yet be considered protective therapy.

3. Phenotypes

Core manifestations

Glaucomatous optic neuropathy—clinical sign; chronic and progressive; commonly bilateral but potentially asymmetric. Suggested HPO: Abnormality of the optic nerve (HP:0000587) and optic atrophy (HP:0000648; verify current HPO label/ID before ingestion).
Optic-disc excavation/increased cup-to-disc ratio—clinical sign detected by fundoscopy/OCT. Suggested HPO: Increased cup-to-disc ratio (HP:0001138).
RNFL thinning and RGC loss—structural signs; progressive and irreversible. Suggested HPO: abnormal retinal morphology/RNFL thinning; use exact current HPO child after ontology validation.
Visual-field defect—functional sign, initially often arcuate, paracentral, or nasal-step loss; may advance to severe constriction. Suggested HPO: Visual field defect (HP:0001123; validate current ID).
Reduced vision/blindness—late morbidity rather than an early symptom. Suggested HPO: Visual impairment and blindness.
Normal untreated IOP—laboratory/physiologic characteristic in the predominant NTG presentation, conventionally consistently <21 mmHg. (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2)
Open anterior-chamber angle—gonioscopic sign required for classification as open-angle disease. (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2)

Onset, frequency, severity, and progression

Disease is generally adult-onset, insidious, chronic, and progressive. E50K expression was age-dependent in the landmark family, with segregation reported in affected people older than 30 years. Exact median onset, sex ratio, bilateral frequency, and phenotype-specific percentages have not been robustly established for molecularly confirmed OPTN cases. E50K has repeatedly been described as the most severe OPTN glaucoma allele, but quantitative genotype-specific natural-history datasets remain small. (swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)

Patients may be asymptomatic until substantial field loss occurs. Severity varies from mild structural damage to advanced, disabling visual-field loss and blindness. There is no episodic or relapsing-remitting pattern and no spontaneous restoration of dead RGCs.

Quality of life

Loss of peripheral and central visual field affects mobility, driving, reading, fall risk, independence, and psychological well-being. The chronic threat of irreversible blindness and the burden of lifelong drops and surveillance further reduce quality of life. No EQ-5D, SF-36, PROMIS, or glaucoma-specific quality-of-life dataset restricted to OPTN carriers was identified. General glaucoma evidence should therefore be labeled indirect. (salvetat2023pharmaceuticalapproachesto pages 1-2, tsai2024glaucomaanimalmodels pages 1-2)

4. Genetic and molecular information

Gene and protein

OPTN encodes a 577-amino-acid adaptor containing coiled-coil regions, an LC3-interacting region, a ubiquitin-binding domain and a C-terminal zinc finger. It is expressed in retina, brain and multiple other tissues and participates in vesicular trafficking, autophagy, mitophagy, innate immune signaling and cellular homeostasis. Relevant partners include TBK1, LC3, RAB8, myosin VI, TBC1D17, huntingtin and transferrin receptor. (venkatesan2025proteinmisfoldingand pages 6-7, swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)

Pathogenic-variant curation

Variant	Evidence-based interpretation	Functional consequence
E50K, p.Glu50Lys	Best-supported dominant pathogenic allele; family segregation plus animal and human-cell validation	Altered/misfolded oligomers, increased TBK1/RAB8 interactions, impaired endosomal recycling and autophagic-lysosomal clearance; RGC-selective degeneration (venkatesan2025proteinmisfoldingand pages 8-9, venkatesan2025proteinmisfoldingand pages 6-7, nagabhushana2010regulationofendocytic pages 1-2)
M98K, p.Met98Lys	Population-dependent susceptibility/modifier; not equivalent to E50K	Increased TBK1 activation and Ser177 phosphorylation, excessive autophagosome formation, transferrin-receptor degradation and autophagy-dependent retinal-cell death in vitro (swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)
H26D, E322K, H486R, R545Q and others	Reported associations; classification requires current ClinVar submission-level review, population frequency, segregation and functional evidence	Variable or incompletely established (rozpedekkaminska2020thegeneticand pages 26-28, venkatesan2025proteinmisfoldingand pages 8-9)

Most reported glaucoma alleles are missense. The disease is germline, not somatic. Precise gnomAD/TOPMed frequencies and current ClinVar classifications could not be verified with the available tools and should not be inferred. Similarly, no recurrent pathogenic large chromosomal rearrangement at OPTN was established; TBK1 duplication is a separate NTG cause.

Penetrance, modifiers, and epigenetics

Penetrance is incomplete and age-dependent, but no reliable numeric penetrance curve is available. Expressivity is variable. Anticipation, germline mosaicism, consanguinity effects, and a specific founder effect have not been established. No validated OPTN-specific DNA-methylation or histone-modification biomarker is available. Reported microRNA/long-noncoding-RNA changes in E50K mice are exploratory and not clinical epigenetic tests.

5. Environmental information

There is no infectious agent, toxin, radiation exposure, or occupational exposure known to be necessary or sufficient. General NTG literature implicates vascular insufficiency, disturbed autoregulation, nocturnal hypotension, vasospasm, transient hypoxia, oxidative stress and possibly sleep apnea. Smoking and high BMI have been associated with glaucoma-related traits, but neither is an OPTN-specific causal exposure. (mallick2016updateonnormal pages 1-2)

No vaccine or antimicrobial intervention is applicable.

6. Mechanism and pathophysiology

Integrated causal chain

Upstream trigger: heterozygous mutant OPTN—most convincingly E50K—alters OPTN conformation, localization and partner binding.

Intermediate cellular defects:

Vesicular trafficking failure. In vitro, E50K enlarged recycling endosomes, slowed mutant vesicle dynamics, reduced transferrin uptake, enhanced association with RAB8/transferrin receptor and slowed RAB8 vesicles. The authors concluded: “The E50K mutant impairs trafficking at the recycling endosomes due to altered interactions with Rab8 and transferrin receptor.” DOI 10.1186/1471-2121-11-4, published January 2010. (nagabhushana2010regulationofendocytic pages 1-2)
OPTN–TBK1/autophagy dysregulation. TBK1 phosphorylates OPTN near its LC3-interacting region, enhancing cargo capture. E50K can enhance OPTN–TBK1 interaction and disturb RAB8 trafficking/autophagosome formation. M98K experimentally activates TBK1 and increases Ser177-dependent autophagosome formation and retinal-cell death; TBK1 knockdown or inhibition reduced these effects. (venkatesan2025proteinmisfoldingand pages 6-7, sirohi2015aglaucomaassociatedvariant pages 1-2)
Autophagic-lysosomal failure and altered mitophagy. OPTN normally links ubiquitinated cargo and damaged mitochondria to LC3-positive autophagosomes. E50K can reduce effective cargo clearance and promote protein accumulation, whereas M98K may drive maladaptive excessive autophagic degradation. Thus “more” versus “less” autophagy is context- and variant-dependent; autophagic flux, rather than static LC3 abundance, is the relevant measure. (venkatesan2025proteinmisfoldingand pages 8-9, huang2024acquisitionofneurodegenerative pages 1-2, sirohi2015aglaucomaassociatedvariant pages 1-2)
Energy-stress signaling. The major 2024 development was an isogenic human hPSC-RGC study. Its abstract states: “We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor AMPK, along with subsequent neurodegeneration in OPTN(E50K) RGCs.” Pharmacologic mTORC1 inhibition produced disease-like changes in control RGCs, while mTOR-independent autophagy induction reduced protein accumulation and restored neurite outgrowth. Acta Neuropathologica Communications, 16 October 2024, DOI 10.1186/s40478-024-01872-2. (huang2024acquisitionofneurodegenerative pages 1-2)
Mitochondrial dysfunction, oxidative stress and apoptosis. Defective mitophagy permits damaged mitochondria, energetic failure and reactive-oxygen stress; downstream caspase activation, neurite retraction and RGC death follow. RGCs are especially vulnerable because of their long axons and high energetic demand. (venkatesan2025proteinmisfoldingand pages 8-9, huang2023elucidatingcellularmechanisms pages 46-51, tsai2024glaucomaanimalmodels pages 1-2)
Glial/inflammatory amplification. E50K mice display persistent reactive gliosis. General glaucoma models implicate microglia, astrocytes, innate immunity and oxidative/ischemic injury; direct OPTN-specific human inflammatory evidence remains limited. (tsai2024glaucomaanimalmodels pages 1-2, swarup2018alteredfunctionsand pages 1-3)

Clinical endpoint: progressive RGC somal and axonal loss → RNFL thinning and optic-disc cupping → corresponding visual-field loss → irreversible visual disability/blindness.

Ontology suggestions

GO biological processes: autophagy (GO:0006914), mitophagy (GO:0000422), autophagosome assembly (GO:0000045), endocytic recycling, intracellular vesicle-mediated transport, protein phosphorylation, apoptotic process (GO:0006915), inflammatory response (GO:0006954), response to oxidative stress (GO:0006979).
GO cellular components: Golgi apparatus (GO:0005794), endosome (GO:0005768), autophagosome (GO:0005776), lysosome (GO:0005764), mitochondrion (GO:0005739).
Cell Ontology: retinal ganglion cell (CL:0000740), astrocyte (CL:0000127); retinal microglial and trabecular-meshwork cell IDs should be checked against the current CL release.

Molecular profiling and advanced technologies

The 2023 precursor hPSC-RGC work found 75 downregulated and 117 upregulated genes, with changes involving protein clearance, trafficking and neurite outgrowth; mutant cells also showed LC3 accumulation, active caspase-3 elevation and increased excitability. (huang2023elucidatingcellularmechanisms pages 39-46, huang2023elucidatingcellularmechanisms pages 46-51)

The 2024 study used isogenic CRISPR-edited embryonic-stem-cell and patient-iPSC pairs, RGC differentiation, autophagy sensors, immunoblotting, microscopy and morphometry. Trehalose treatment restored neurite morphology and shifted LC3-II and pS6 toward control values; for example, reported treatment comparisons included p=0.03 for LC3-II and p=0.029 for pS6. (huang2024acquisitionofneurodegenerative pages 14-16, huang2023elucidatingcellularmechanisms pages 82-86, huang2024acquisitionofneurodegenerative pages 16-18)

No validated OPTN-specific clinical single-cell, spatial-transcriptomic, proteomic, metabolomic or lipidomic signature was identified. These remain research opportunities.

7. Anatomical structures affected

Organ: eye; secondary extension along the central visual pathway may occur as a consequence of optic-nerve degeneration.
Primary tissues: neural retina/RNFL, optic-nerve head including lamina region, and optic nerve.
Principal cell: RGC; secondary reactive cells include astrocytes and microglia. Trabecular-meshwork cells are relevant to conventional POAG and OPTN/MYOC interactions, but E50K NTG is principally an RGC/optic-nerve disease. (trivli2020primaryopenangle pages 1-2, huang2024acquisitionofneurodegenerative pages 1-2, tsai2024glaucomaanimalmodels pages 1-2)
Suggested UBERON: retina UBERON:0000966; optic nerve UBERON:0000978. Validate optic-nerve-head, RNFL and trabecular-meshwork child terms before ingestion.
Subcellular sites: Golgi, recycling endosome, autophagosome, lysosome and mitochondrion.
Lateralization: commonly bilateral, often asymmetric; robust OPTN-specific proportions are unavailable.

8. Temporal development

The typical course is adult-onset and insidious. A genetically susceptible RGC may compensate for decades before aging, metabolic demand, vascular stress or declining proteostasis crosses a threshold. Early disease consists of OCT/RNFL or optic-disc changes with little subjective impairment; intermediate disease shows reproducible field loss; advanced disease threatens fixation and functional independence. Disease is chronic and lifelong, with variable progression. (salvetat2023pharmaceuticalapproachesto pages 1-2, swarup2018alteredfunctionsand pages 1-3)

There is no spontaneous remission. IOP-lowering treatment can slow progression, but cannot restore dead RGCs. The critical intervention window is therefore before substantial RNFL and field loss, supporting cascade testing and surveillance of at-risk relatives.

9. Inheritance and population

Inheritance

The best-established pattern is autosomal dominant with age-dependent, incomplete penetrance and variable expressivity. Each child of a heterozygous carrier has a 50% probability of inheriting the variant, although inheritance does not predict age of onset or severity. Genetic anticipation is not established. (swarup2018alteredfunctionsand pages 1-3)

Epidemiology

A disease-specific prevalence or incidence per 100,000 has not been established. Reviews estimate that approximately 5% of all POAG is Mendelian, whereas OPTN mutations explain approximately 1% or less of sporadic NTG and around 1–2% of POAG in some summaries. These estimates vary by ancestry, ascertainment and variant interpretation. (trivli2020primaryopenangle pages 1-2, swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)

For context—not OPTN-specific—NTG represents about 20–40% of POAG in Caucasian or African populations and 47–92% in some Asian POAG series. A 2023 review estimated NTG at 30–40% of all glaucoma cases. These figures must not be used as OPTN prevalence. (salvetat2023pharmaceuticalapproachesto pages 1-2)

M98K association appears ancestry-dependent, stronger in some Asian datasets. No reliable carrier frequency, sex ratio, founder distribution, or geographic incidence for pathogenic E50K was identified. Consanguinity is not expected to be a major determinant of a dominant disorder.

10. Diagnostics

Clinical diagnosis

A diagnosis requires evidence that the eye truly has glaucoma and that the angle is open, while excluding mimics. Core investigations are:

history, pedigree, medication and vascular-risk review;
repeated Goldmann applanation tonometry, preferably including diurnal assessment when indicated;
pachymetry because thin cornea can cause IOP underestimation;
gonioscopy confirming an open angle;
dilated stereoscopic optic-disc examination and photography;
OCT of peripapillary RNFL and macular ganglion-cell complex;
standard automated perimetry, repeated to establish a reproducible defect and progression;
selected blood-pressure monitoring, neuroimaging or neuro-ophthalmic assessment when the pattern is atypical. (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2)

Direct abstract quote: “Goldmann applanation tonometry, gonioscopy, slit lamp biomicroscopy, optical coherence tomography and visual field analysis are the main tools of investigation for the diagnosis of NTG.” DOI 10.4103/2008-322X.183914, published April 2016. (mallick2016updateonnormal pages 1-2)

Genetic testing

A multigene glaucoma panel is generally preferable to isolated OPTN sequencing for familial NTG, early-onset disease, or a strong pedigree. At minimum, relevant genes include OPTN, TBK1 with deletion/duplication analysis, MYOC, WDR36 and CYP1B1, with broader validated panels adding other glaucoma/optic-neuropathy genes. Sanger confirmation and family segregation are particularly important for non-E50K findings.

A 2024 72-gene panel study found nine rare variants in 16% of 61 POAG patients, distributed across CYP1B1, SIX6, CARD10, MFN1, OPTC, OPTN and WDR36. The authors cautioned that segregation and functional work are needed to establish contribution. PLOS ONE, 19 January 2024, DOI 10.1371/journal.pone.0282133. (milla2024nextgenerationsequencingbasedgene pages 1-2)

Single-gene sequencing: reasonable when a known familial OPTN variant is present.
Panel: preferred first-line assay in genetically heterogeneous glaucoma.
WES/WGS: useful when panel testing is negative in a strongly familial case; WGS may detect noncoding or structural variants but interpretation remains difficult.
CMA/karyotype/FISH: not routine; targeted copy-number testing is more appropriate for TBK1.
Mitochondrial DNA and repeat-expansion testing: not routine for classic OPTN glaucoma, but may be used for an alternative inherited optic-neuropathy phenotype.
RNA/proteomics/metabolomics/liquid biopsy: research only.

Differential diagnosis

Exclude ocular hypertension without neuropathy, high-tension POAG with missed peaks, angle-closure or secondary glaucoma, physiologic cupping, high-myopia-related disc changes, ischemic or compressive optic neuropathy, optic neuritis, hereditary optic atrophy (e.g., OPA1) and mitochondrial optic neuropathy. Atypical pallor exceeding cupping, marked color-vision loss, vertical-meridian field defects, rapid decline, pain, or neurologic signs should prompt neuro-ophthalmic investigation.

Screening

There is no newborn screening. Offer cascade variant testing and lifelong ophthalmic surveillance to adult relatives when a pathogenic familial variant is known. A negative test for the familial variant substantially reduces that monogenic risk but does not eliminate ordinary population POAG risk.

11. Outcome and prognosis

OPTN glaucoma affects morbidity rather than general survival. No disease-specific mortality or reduced life expectancy is established. Visual prognosis depends on baseline damage, age, rate of RNFL/field loss, IOP achieved, adherence, vascular factors and treatment response.

Untreated progression can produce irreversible bilateral visual disability or blindness. Lowering IOP reduces risk but does not eliminate it, because OPTN-linked autophagic, mitochondrial and axonal mechanisms are not directly corrected. No validated molecular prognostic biomarker beyond genotype itself exists. E50K may signal a relatively severe phenotype, but current data do not support a precise individualized progression calculator. (salvetat2023pharmaceuticalapproachesto pages 1-2, swarup2018alteredfunctionsand pages 1-3)

Recovery of lost RGCs or established visual field is not expected with present care. Treatment aims to preserve remaining function.

12. Treatment

Standard clinical management

There is no approved OPTN-specific therapy. Management follows NTG/POAG algorithms:

establish baseline structural and functional damage and an individualized target IOP;
lower IOP even if it begins in the normal range—often approximately 30% below untreated baseline, commonly toward 12–14 mmHg when safely achievable;
reassess OCT, disc and visual fields and lower the target further if progression continues;
address adherence, drop technique, nocturnal hypotension and relevant systemic/vascular factors;
escalate to laser or surgery when drops are inadequate or poorly tolerated. (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2)

Pharmacotherapy

Prostaglandin analogues—increase uveoscleral outflow; generally first-line.
Beta-blockers—reduce aqueous production; monitor bradycardia, bronchospasm and nocturnal hypotension.
Alpha-2 agonists such as brimonidine—reduce production and increase outflow.
Topical carbonic-anhydrase inhibitors—reduce aqueous production.
Rho-kinase inhibitors—increase trabecular outflow where approved.
Fixed combinations may reduce bottle burden.

Suggested NCIt intervention concepts: pharmacologic IOP reduction, prostaglandin analogue therapy, beta-adrenergic antagonist therapy, carbonic-anhydrase inhibitor therapy and alpha-2 adrenergic agonist therapy; exact NCIt codes should be checked against the current release.

Adverse effects include ocular hyperemia/irritation, surface disease, prostaglandin-associated iris/periocular changes, beta-blocker cardiopulmonary effects and alpha-agonist allergy or fatigue. No OPTN pharmacogenomic dosing guideline exists.

Laser and surgery

Selective laser trabeculoplasty can be considered when sufficient trabecular outflow reserve exists, although absolute pressure reduction may be limited at low baseline IOP. Trabeculectomy, tube surgery and selected minimally invasive glaucoma surgery are options when progression continues, but NTG requires careful balancing of very low target pressure against hypotony risk. (tsai2024glaucomaanimalmodels pages 1-2)

Suggested NCIt concepts: laser trabeculoplasty, trabeculectomy, glaucoma drainage-device implantation, and minimally invasive glaucoma surgery.

Experimental precision therapies

Autophagy modulation: in 2024 human E50K RGCs, mTOR-independent induction with trehalose reduced protein accumulation and restored neurite outgrowth. This is preclinical and does not justify clinical trehalose prescribing. (huang2024acquisitionofneurodegenerative pages 18-20, huang2024acquisitionofneurodegenerative pages 14-16)
TBK1 modulation: TBK1 inhibition reduced M98K-driven autophagy/cell death in vitro, but systemic TBK1 has important immune functions, creating on-target safety concerns. (swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)
Mitochondrial/neuroprotective therapies: antioxidants, metabolic support, caspase inhibition and regenerative RGC strategies remain experimental.
Gene replacement/editing, ASO/siRNA and cell replacement: no validated OPTN clinical implementation. Dominant altered-function E50K may require allele-specific silencing or correction rather than simple gene addition.

The clinical-trial search returned no relevant OPTN-directed glaucoma interventional trial and no NCT identifier suitable for inclusion. This negative result should be periodically rechecked.

13. Prevention

Primary prevention

The inherited allele cannot currently be prevented after conception. No vaccine, chemoprophylaxis or proven lifestyle program prevents disease in carriers. Reproductive options after counseling may include prenatal diagnosis or preimplantation genetic testing when a clearly pathogenic familial variant is known; these are individual choices, not treatment recommendations.

Secondary prevention

This is the most actionable level: cascade genetic testing, periodic tonometry, gonioscopy, disc photography, OCT and perimetry can identify presymptomatic structural change and permit early pressure lowering. Testing should focus on a known familial pathogenic variant or use a validated panel when the familial cause is unknown.

Tertiary prevention

Adherence to IOP-lowering treatment, serial progression analysis, low-vision referral when needed, fall-risk reduction, driving assessment and timely laser/surgery help prevent advanced disability. Review excessive nocturnal antihypertensive effects and treat relevant sleep or vascular disorders in coordination with the patient’s physician; evidence remains general NTG rather than OPTN-specific. (mallick2016updateonnormal pages 1-2)

14. Other species and natural disease

Homo sapiens: NCBI Taxon 9606; human OPTN is the disease gene.

No well-established naturally occurring OPTN-related glaucoma syndrome in a companion-animal breed or wildlife population was identified. Accordingly, no VBO breed annotation, veterinary prevalence or zoonotic significance can be assigned. The disease is noninfectious and nontransmissible.

OPTN structure and autophagy functions are evolutionarily conserved, permitting mouse and vertebrate experimental modeling. This conservation is mechanistically valuable, but species differences in RGC subtype composition, optic-nerve anatomy and lifespan limit direct prediction of human penetrance and treatment response. (huang2024acquisitionofneurodegenerative pages 1-2, tsai2024glaucomaanimalmodels pages 1-2)

15. Model organisms and experimental systems

Mouse models

E50K transgenic and knock-in mice, Mus musculus (Taxon 10090): reproduce RGC loss, retinal/optic-nerve injury and reactive gliosis without requiring chronic IOP elevation; useful for NTG neurodegeneration, inflammation, autophagy and neuroprotection. (tsai2024glaucomaanimalmodels pages 1-2, swarup2018alteredfunctionsand pages 1-3)
Limitations: expression level and promoter may not match the human heterozygous state; mice lack a human-like macula and have different RGC subtype distributions. Reviews emphasize that each glaucoma model captures only part of human disease. (tsai2024glaucomaanimalmodels pages 1-2)

Human stem-cell models

Isogenic CRISPR-edited hESC/iPSC-derived RGCs carrying E50K are the strongest recent human model. They show normal initial RGC generation followed by smaller somata, reduced neurite complexity/length, altered excitability, OPTN/protein accumulation, impaired autophagic-lysosomal degradation, AMPK activation and reduced mTORC1 signaling. Correction or isogenic wild-type comparators reduce background-genome confounding. (huang2023elucidatingcellularmechanisms pages 39-46, huang2024acquisitionofneurodegenerative pages 1-2)

Their main applications are causal-pathway analysis, temporal profiling and phenotype-based drug screening. Limitations include developmental immaturity, absence of full lamina/vascular/immune architecture and incomplete modeling of decades-long aging.

Conventional cell systems

HeLa and retinal-cell cultures have established trafficking and TBK1/autophagy mechanisms. However, the historical RGC-5 line has identity and differentiation limitations, and findings should be confirmed in primary RGCs, human isogenic RGCs or in vivo models. (swarup2018alteredfunctionsand pages 1-3, nagabhushana2010regulationofendocytic pages 1-2)

Other induced models

Ocular-hypertension, optic-nerve-crush, ischemia–reperfusion, excitotoxic and autoimmune glaucoma models help dissect downstream injury but do not reproduce the initiating OPTN genotype. The 2024 hPSC study validated selected autophagy findings in a mouse ocular-hypertension model, supporting pathway convergence across genetic and pressure-mediated glaucoma. (huang2024acquisitionofneurodegenerative pages 14-16, tsai2024glaucomaanimalmodels pages 1-2)

Evidence assessment and critical gaps

High confidence: OPTN is linked to GLC1E/open-angle glaucoma; E50K is the best-supported dominant allele; the core phenotype is frequently NTG; RGC/optic-nerve degeneration and trafficking/autophagy dysfunction are central.
Moderate confidence: E50K generally confers severe, age-dependent disease and TBK1/mitochondrial pathways materially contribute.
Low or variant-dependent confidence: pathogenicity of M98K, H486R, R545Q and many rare variants; precise penetrance; founder effects and ancestry-specific risk.
Major missing data: molecularly confirmed prevalence/incidence, prospective carrier natural history, allele-frequency tables, genotype-specific treatment response, quality-of-life measures, protective factors, clinical omics biomarkers and OPTN-directed trials.
Curation rule: do not transfer general NTG statistics or interventions into an OPTN-specific field without labeling them as extrapolated evidence.

Selected primary and recent sources

Rezaie T, et al. Science. 8 February 2002. “Adult-onset primary open-angle glaucoma caused by mutations in optineurin.” PMID 11834836; DOI: 10.1126/science.1066901. (OpenTargets Search: open-angle glaucoma-OPTN, swarup2018alteredfunctionsand pages 1-3)
Nagabhushana A, et al. BMC Cell Biology. January 2010. E50K and endocytic recycling. DOI: 10.1186/1471-2121-11-4. (nagabhushana2010regulationofendocytic pages 1-2)
Sirohi K, et al. PLOS ONE. 16 September 2015. M98K–TBK1–Ser177/autophagy mechanism. DOI: 10.1371/journal.pone.0138289. (sirohi2015aglaucomaassociatedvariant pages 1-2)
Salvetat ML, et al. Pharmaceuticals. 17 August 2023. Current NTG treatment review. DOI: 10.3390/ph16081172. (salvetat2023pharmaceuticalapproachesto pages 1-2)
Milla E, et al. PLOS ONE. 19 January 2024. Adult-glaucoma NGS panel study. DOI: 10.1371/journal.pone.0282133. (milla2024nextgenerationsequencingbasedgene pages 1-2)
Tsai T, et al. International Journal of Molecular Sciences. 11 January 2024. Animal models beyond chronic IOP elevation. DOI: 10.3390/ijms25020906. (tsai2024glaucomaanimalmodels pages 1-2)
Huang KC, et al. Acta Neuropathologica Communications. October 2024. Isogenic OPTN(E50K) human RGCs, autophagy and mTORC1. DOI: 10.1186/s40478-024-01872-2. (huang2024acquisitionofneurodegenerative pages 18-20, huang2024acquisitionofneurodegenerative pages 1-2)

References

(trivli2020primaryopenangle pages 1-2): Alexandra Trivli, Maria Zervou, George Goulielmos, Demetrios Spandidos, and Efstathios Detorakis. Primary open angle glaucoma genetics: the common variants and their clinical associations. Molecular Medicine Reports, 22:1103-1110, Jun 2020. URL: https://doi.org/10.3892/mmr.2020.11215, doi:10.3892/mmr.2020.11215. This article has 47 citations and is from a peer-reviewed journal.
(salvetat2023pharmaceuticalapproachesto pages 1-2): Maria Letizia Salvetat, Francesco Pellegrini, Leopoldo Spadea, Carlo Salati, and Marco Zeppieri. Pharmaceutical approaches to normal tension glaucoma. Pharmaceuticals, 16:1172, Aug 2023. URL: https://doi.org/10.3390/ph16081172, doi:10.3390/ph16081172. This article has 39 citations.
(swarup2018alteredfunctionsand pages 1-3): Ghanshyam Swarup and Zuberwasim Sayyad. Altered functions and interactions of glaucoma-associated mutants of optineurin. Frontiers in Immunology, Jun 2018. URL: https://doi.org/10.3389/fimmu.2018.01287, doi:10.3389/fimmu.2018.01287. This article has 86 citations and is from a peer-reviewed journal.
(sirohi2015aglaucomaassociatedvariant pages 1-2): Kapil Sirohi, Asha Kumari, Vegesna Radha, and Ghanshyam Swarup. A glaucoma-associated variant of optineurin, m98k, activates tbk1 to enhance autophagosome formation and retinal cell death dependent on ser177 phosphorylation of optineurin. PLOS ONE, 10:e0138289, Sep 2015. URL: https://doi.org/10.1371/journal.pone.0138289, doi:10.1371/journal.pone.0138289. This article has 54 citations and is from a peer-reviewed journal.
(OpenTargets Search: open-angle glaucoma-OPTN): Open Targets Query (open-angle glaucoma-OPTN, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(milla2024nextgenerationsequencingbasedgene pages 1-2): Elena Milla, Javier Laguna, Mª. Socorro Alforja, Beatriz Pascual, María José Gamundi, Emma Borràs, Imma Hernán, María Jesús Muniesa, Marta Pazos, Susana Duch, Miguel Carballo, and Meritxell Jodar. Next-generation sequencing-based gene panel tests for the detection of rare variants and hypomorphic alleles associated with primary open-angle glaucoma. PLOS ONE, 19:e0282133, Jan 2024. URL: https://doi.org/10.1371/journal.pone.0282133, doi:10.1371/journal.pone.0282133. This article has 6 citations and is from a peer-reviewed journal.
(rozpedekkaminska2020thegeneticand pages 26-28): Wioletta Rozpędek-Kamińska, Radosław Wojtczak, Jacek P. Szaflik, Jerzy Szaflik, and Ireneusz Majsterek. The genetic and endoplasmic reticulum-mediated molecular mechanisms of primary open-angle glaucoma. International Journal of Molecular Sciences, 21:4171, Jun 2020. URL: https://doi.org/10.3390/ijms21114171, doi:10.3390/ijms21114171. This article has 31 citations.
(venkatesan2025proteinmisfoldingand pages 8-9): Arunkumar Venkatesan and Audrey M. Bernstein. Protein misfolding and mitochondrial dysfunction in glaucoma. Frontiers in Cell and Developmental Biology, Apr 2025. URL: https://doi.org/10.3389/fcell.2025.1595121, doi:10.3389/fcell.2025.1595121. This article has 20 citations.
(nagabhushana2010regulationofendocytic pages 1-2): Ananthamurthy Nagabhushana, Madhavi L Chalasani, Nishant Jain, Vegesna Radha, Nandini Rangaraj, Dorairajan Balasubramanian, and Ghanshyam Swarup. Regulation of endocytic trafficking of transferrin receptor by optineurin and its impairment by a glaucoma-associated mutant. BMC Cell Biology, 11:4-4, Jan 2010. URL: https://doi.org/10.1186/1471-2121-11-4, doi:10.1186/1471-2121-11-4. This article has 133 citations.
(huang2024acquisitionofneurodegenerative pages 1-2): Kang-Chieh Huang, Cátia Gomes, Yukihiro Shiga, Nicolas Belforte, Kirstin B. VanderWall, Sailee S. Lavekar, Clarisse M. Fligor, Jade Harkin, Shelby M. Hetzer, Shruti V. Patil, Adriana Di Polo, and Jason S. Meyer. Acquisition of neurodegenerative features in isogenic optn(e50k) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mtorc1 signaling reduction. Acta Neuropathologica Communications, Oct 2024. URL: https://doi.org/10.1186/s40478-024-01872-2, doi:10.1186/s40478-024-01872-2. This article has 10 citations and is from a peer-reviewed journal.
(mallick2016updateonnormal pages 1-2): Jyotiranjan Mallick, Lily Devi, PradeepK Malik, and Jogamaya Mallick. Update on normal tension glaucoma. Journal of Ophthalmic & Vision Research, 11:204-208, Apr 2016. URL: https://doi.org/10.4103/2008-322x.183914, doi:10.4103/2008-322x.183914. This article has 213 citations and is from a peer-reviewed journal.
(tsai2024glaucomaanimalmodels pages 1-2): Teresa Tsai, Sabrina Reinehr, Leonie Deppe, Alexandra Strubbe, Nils Kluge, H. Burkhard Dick, and Stephanie C. Joachim. Glaucoma animal models beyond chronic iop increase. International Journal of Molecular Sciences, 25:906, Jan 2024. URL: https://doi.org/10.3390/ijms25020906, doi:10.3390/ijms25020906. This article has 25 citations.
(venkatesan2025proteinmisfoldingand pages 6-7): Arunkumar Venkatesan and Audrey M. Bernstein. Protein misfolding and mitochondrial dysfunction in glaucoma. Frontiers in Cell and Developmental Biology, Apr 2025. URL: https://doi.org/10.3389/fcell.2025.1595121, doi:10.3389/fcell.2025.1595121. This article has 20 citations.
(huang2024acquisitionofneurodegenerative pages 18-20): Kang-Chieh Huang, Cátia Gomes, Yukihiro Shiga, Nicolas Belforte, Kirstin B. VanderWall, Sailee S. Lavekar, Clarisse M. Fligor, Jade Harkin, Shelby M. Hetzer, Shruti V. Patil, Adriana Di Polo, and Jason S. Meyer. Acquisition of neurodegenerative features in isogenic optn(e50k) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mtorc1 signaling reduction. Acta Neuropathologica Communications, Oct 2024. URL: https://doi.org/10.1186/s40478-024-01872-2, doi:10.1186/s40478-024-01872-2. This article has 10 citations and is from a peer-reviewed journal.
(huang2023elucidatingcellularmechanisms pages 46-51): Kang-Chieh Huang. Elucidating cellular mechanisms underlying retinal ganglion cell neurodegeneration in a human pluripotent stem cell-derived model. Text, Jan 2023. URL: https://doi.org/10.25394/pgs.21585657.v1, doi:10.25394/pgs.21585657.v1. This article has 0 citations and is from a peer-reviewed journal.
(huang2024acquisitionofneurodegenerative pages 14-16): Kang-Chieh Huang, Cátia Gomes, Yukihiro Shiga, Nicolas Belforte, Kirstin B. VanderWall, Sailee S. Lavekar, Clarisse M. Fligor, Jade Harkin, Shelby M. Hetzer, Shruti V. Patil, Adriana Di Polo, and Jason S. Meyer. Acquisition of neurodegenerative features in isogenic optn(e50k) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mtorc1 signaling reduction. Acta Neuropathologica Communications, Oct 2024. URL: https://doi.org/10.1186/s40478-024-01872-2, doi:10.1186/s40478-024-01872-2. This article has 10 citations and is from a peer-reviewed journal.
(huang2024acquisitionofneurodegenerative pages 16-18): Kang-Chieh Huang, Cátia Gomes, Yukihiro Shiga, Nicolas Belforte, Kirstin B. VanderWall, Sailee S. Lavekar, Clarisse M. Fligor, Jade Harkin, Shelby M. Hetzer, Shruti V. Patil, Adriana Di Polo, and Jason S. Meyer. Acquisition of neurodegenerative features in isogenic optn(e50k) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mtorc1 signaling reduction. Acta Neuropathologica Communications, Oct 2024. URL: https://doi.org/10.1186/s40478-024-01872-2, doi:10.1186/s40478-024-01872-2. This article has 10 citations and is from a peer-reviewed journal.
(huang2023elucidatingcellularmechanisms pages 39-46): Kang-Chieh Huang. Elucidating cellular mechanisms underlying retinal ganglion cell neurodegeneration in a human pluripotent stem cell-derived model. Text, Jan 2023. URL: https://doi.org/10.25394/pgs.21585657.v1, doi:10.25394/pgs.21585657.v1. This article has 0 citations and is from a peer-reviewed journal.
(huang2023elucidatingcellularmechanisms pages 82-86): Kang-Chieh Huang. Elucidating cellular mechanisms underlying retinal ganglion cell neurodegeneration in a human pluripotent stem cell-derived model. Text, Jan 2023. URL: https://doi.org/10.25394/pgs.21585657.v1, doi:10.25394/pgs.21585657.v1. This article has 0 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	14
Resolved	14
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	14
On topic	6
Off topic	0

All extracted references resolved successfully.

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Related Datasets

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

OPTN-Related Open-Angle Glaucoma: Disease-Characteristics Research Report

Executive summary

1. Disease information

Definition and scope

Identifiers and synonyms

Landmark discovery

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

Genetic risk factors

Environmental and systemic modifiers

Protective factors

3. Phenotypes

Core manifestations

Onset, frequency, severity, and progression

Quality of life

4. Genetic and molecular information

Gene and protein

Pathogenic-variant curation

Penetrance, modifiers, and epigenetics

5. Environmental information

6. Mechanism and pathophysiology

Integrated causal chain

Ontology suggestions

Molecular profiling and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

Inheritance

Epidemiology

10. Diagnostics

Clinical diagnosis

Genetic testing

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment

Standard clinical management

Pharmacotherapy

Laser and surgery

Experimental precision therapies

13. Prevention

Primary prevention

Secondary prevention

Tertiary prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Mouse models

Human stem-cell models

Conventional cell systems

Other induced models

Evidence assessment and critical gaps

Selected primary and recent sources

Artifacts

Reference Validation