PDE6G-Related Retinopathy

Mendelian MONDO:1040034 Pathograph 18 Show in embeddings browser Ophthalmological Disease Retinal Dystrophy Inherited retinal dystrophy

PDE6G-related retinopathy (retinitis pigmentosa 57) is a very rare autosomal recessive, severe early-onset retinitis pigmentosa caused by biallelic loss-of-function variants in PDE6G, which encodes the inhibitory gamma subunit of rod cGMP phosphodiesterase 6 (PDE6). Rod PDE6 is a heterotetramer of one alpha (PDE6A) and one beta (PDE6B) catalytic subunit and two gamma subunits. Although the gamma subunit restrains the catalytic core in the dark, its complete absence does not leave PDE6 constitutively active: in knockout mice the catalytic dimer lacks hydrolytic activity, retinal cGMP rises, and rods degenerate within the first weeks of life, followed by cones. Affected people reported to date have extinguished or severely reduced rod and cone electroretinograms in early childhood, markedly constricted visual fields, bone-spicule pigmentation and cystoid macular edema, with relatively preserved central acuity in childhood. Few affected individuals have been described in the literature; the founder splice-donor variant c.187+1G>T in one extended consanguineous Muslim Arab Israeli family is the best characterized allele. There is no disease-specific treatment.

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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
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Mappings

MONDO
MONDO:0013315 retinitis pigmentosa 57 Not Yet Curated
skos:narrowMatch MONDO
MONDO places retinitis pigmentosa 57 (OMIM:613582) as the single child of MONDO:1040034. Every reported PDE6G case presents as autosomal recessive retinitis pigmentosa, and ClinGen states that RP57 is the only disorder currently associated with PDE6G, so the child is captured as a mapping rather than a separate has_subtypes row.
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Inheritance

1
Autosomal recessive HP:0000007
Affected individuals are homozygous or compound heterozygous for PDE6G loss-of-function alleles; heterozygous parents are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"revealed a homozygous single base change (c.187+1G>T) located in the conserved intron 3 donor splice site of PDE6G. This mutation cosegregated with the disease in the extended family."
Homozygosity mapping in a consanguineous family and cosegregation of a homozygous PDE6G splice variant establish recessive inheritance.
PMID:39160471 SUPPORT PRIMARY RESULT Human clinical
"Analysis of the parental genes showed that frameshift mutation was inherited from the proband's mother and segment deletion from his father."
Compound heterozygosity with one allele from each unaffected parent in a second, unrelated family.
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Discussions and Knowledge Gaps

2
Does loss of the PDE6 gamma subunit leave an inactive but stable catalytic dimer, or does it destabilize the PDE6A/PDE6B subunits themselves, and which applies to the human alleles?
KNOWLEDGE GAP OPEN pde6g_catalytic_subunit_stability
Attached to
pathophysiology#Loss of Rod PDE6 Holoenzyme Catalytic Activity
The two null mouse lines differ: the original neomycin-insertion knockout retained a PDE6A/PDE6B dimer without activity, while the exon 2-3 knockout and the C-terminal Del7C allele lost most catalytic protein. The answer decides whether residual catalytic subunit is present for a gene supplementation approach to work with, and no human tissue or patient-derived retinal model has been studied.
Show evidence (1 reference)
PMID:37363133 SUPPORT PRIMARY RESULT Model organism
"Interestingly, the Pde6gtm1/tm1 mouse line, in which the third exon was replaced with the bacterial neomycin resistance gene, shows a slightly later disease onset, a similarly rapid rate of photoreceptor degeneration (1 row of cone photoreceptors remaining at P21), and assembly, folding, and..."
The later model's authors state the discrepancy with the original knockout directly.
Can human PDE6G missense alleles that weaken inhibition without abolishing the protein cause congenital stationary night blindness instead of retinitis pigmentosa, as some mouse alleles do?
KNOWLEDGE GAP OPEN pde6g_stationary_night_blindness_alleles
Attached to
disease#PDE6G-Related Retinopathy
An allelic series in mice spans stationary night blindness to progressive degeneration, and the gene-discovery authors anticipated that other human alleles might cause stationary night blindness. All reported human alleles are loss of function and cause RP, so the allelic spectrum in humans is untested.
Show evidence (2 references)
PMID:12700134 SUPPORT REVIEW SYNTHESIS Model organism
"we have been studying an allelic series of mutations in the gamma-subunit of the cGMP phosphodiesterase gene (Pdeg) that resulted in visual defects ranging from stationary night blindness to progressive retinal degeneration."
Mouse Pde6g alleles produce either stationary or degenerative disease.
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"Nevertheless, it is possible that different mutant alleles of PDE6G will be discovered in the future in patients with CSNB."
The gene-discovery authors raise the possibility of a human stationary night blindness allele.
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Pathophysiology

5
PDE6G Loss of Function
Reported human alleles remove or truncate the gamma subunit: the founder c.187+1G>T splice-donor variant replaces the last 25 amino acids, which hold the overlapping transducin-binding and catalytic-inhibition regions, with unrelated sequence; a recurrent multi-kilobase deletion removes coding exons 3 and 4; and a frameshift (c.95del) truncates the protein early. ClinGen concludes that the disease mechanism is loss of function. The molecular function bound here is the gamma subunit's own activity as an inhibitor of the PDE6 catalytic core (GO enzyme inhibitor activity, the term GO annotates to PDE6G); its loss paradoxically lowers rather than raises PDE6 activity, as the next node records.
retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
PDE6G hgnc:8789 ↓ DECREASED HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased PDE6G (hgnc:8789). hgnc:8789 is a gene from the HUGO Gene Nomenclature Committee.
PDE6 catalytic subunit inhibitor activity GO:0004857 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased PDE6 catalytic subunit inhibitor activity, annotated with enzyme inhibitor activity (GO:0004857). GO:0004857 is a molecular function from the Gene Ontology.
Downstream
Loss of Rod PDE6 Holoenzyme Catalytic Activity Without a functional gamma subunit, the rod PDE6 catalytic dimer is present in the Pde6g knockout but does not hydrolyze cGMP.
Show evidence (3 references)
PMID:20655036 SUPPORT PRIMARY RESULT In vitro / ex vivo
"We used an in vitro splicing assay to demonstrate that this mutation leads to incorrect splicing."
A minigene splicing assay shows that the founder c.187+1G>T variant disrupts normal PDE6G splicing.
PMID:20655036 SUPPORT PRIMARY RESULT In vitro / ex vivo
"the splicing product obtained from the c.187+1G>T mutant allele encodes for an abnormal Pγ protein in which the last 25 amino acids (D63-I87) are replaced by 52 irrelevant amino acids. The missing amino acids include the overlapping regions responsible for transducin binding and Pαβ inhibition."
Defines the predicted protein consequence of the founder allele: loss of the C-terminal functional domains of the gamma subunit.
CGGV:assertion_b5b69965-33e0-4a8c-b5dd-faede6c39912-2024-06-06T160000.000Z SUPPORT REVIEW SYNTHESIS Other
"The disease mechanism appears to be loss of function."
ClinGen Retina expert panel summary of the gene-disease mechanism.
Loss of Rod PDE6 Holoenzyme Catalytic Activity
The gamma subunit is required not only to inhibit the catalytic core in the dark but also, through its C terminus, for a stable, active holoenzyme. Its absence or C-terminal truncation leaves little or no light-regulated cGMP hydrolysis. Mouse models disagree on whether the catalytic subunits themselves are lost: the original neomycin-insertion knockout kept a PDE6A/PDE6B dimer that lacked activity, whereas a later exon 2-3 knockout and the C-terminal deletion allele lost most PDE6B or PDE6A/PDE6B protein.
retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
3',5'-cyclic-GMP phosphodiesterase activity GO:0047555 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased 3',5'-cyclic-GMP phosphodiesterase activity (GO:0047555). GO:0047555 is a molecular function from the Gene Ontology.
Animal models
Pde6g tm1 knockout mouse Mouse recapitulates Catalytic dimer present but without hydrolytic activity.
Downstream
Rod Outer-Segment cGMP Accumulation Loss of PDE6 activity prevents light from lowering cGMP, and cGMP rises before photoreceptors are lost.
Show evidence (4 references)
PMID:8638127 SUPPORT PRIMARY RESULT Model organism
"Thus, the inhibitory gamma subunit appears to be necessary for integrity of the photoreceptors and expression of PDE activity in vivo."
The knockout study's conclusion that PDE6 activity in vivo requires the gamma subunit.
PMID:11853759 SUPPORT PRIMARY RESULT Model organism
"Instead, our results showed that the Del7C transgene could not complement the Pdeg(tm1)/Pdeg(tm1) mutant for photoreceptor survival. In fact, animals carrying the Del7C transgene have low PDE activity as well as reduced PDEalpha and PDEbeta content."
A gamma subunit lacking its last seven residues fails to rescue the knockout and leaves low PDE activity with reduced catalytic subunits, which is the class of defect the human founder allele (C-terminal replacement) is predicted to cause.
PMID:37363133 SUPPORT PRIMARY RESULT Model organism
"we immunolabeled sections for PDE6B and found that, like PDE6G, PDE6B immunolabeling was not detectable in Pde6g−/− retinas"
In the exon 2-3 knockout the PDE6B catalytic subunit is also lost from rod outer segments.
+ 1 more reference
Rod Outer-Segment cGMP Accumulation
Retinal cGMP is elevated in Pde6g knockout mice and the rise precedes photoreceptor degeneration. The proposed consequence is that cGMP-gated cation channels stay open, imposing a sustained ion and energy load on rods. That last step is the authors' hypothesis rather than a measurement.
retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
Downstream
Early-Onset Rod Photoreceptor Degeneration Persistently high cGMP is proposed to keep cGMP-gated channels open and overload rods, resulting in their degeneration.
Show evidence (1 reference)
PMID:8638127 SUPPORT PRIMARY RESULT Model organism
"Moreover, the increase in cGMP levels preceded photoreceptor degeneration"
Shows cGMP elevation in the knockout retina before photoreceptor loss, placing it upstream of degeneration.
Early-Onset Rod Photoreceptor Degeneration
Rod outer segments fail to develop normally and rods are lost within the first two to three postnatal weeks in Pde6g knockout mice. In patients, rod-driven electroretinogram responses are already extinguished or severely reduced by about 4 years of age, matching the severe early-onset course.
retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
photoreceptor cell outer segment organization GO:0035845 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased photoreceptor cell outer segment organization (GO:0035845). GO:0035845 is a biological process from the Gene Ontology.
Animal models
Pde6g tm1 knockout mouse Mouse recapitulates Photoreceptor layer lost by 8 weeks of age.
Downstream
Secondary Cone Degeneration and Retinal Remodeling Cone loss follows rod loss, and rod loss drives remodeling of inner retinal neurons, glia, vasculature and retinal pigment epithelium.
Constriction of peripheral visual field
Show evidence (4 references)
PMID:8638127 SUPPORT PRIMARY RESULT Model organism
"Transmission electron microscopy revealed that the photoreceptor outer segments had failed to develop normally and were disorganized at postnatal day 10 (P10), and that most of the outer segments were lost by P13, although the photoreceptor nuclear layer remained intact"
Outer segment maldevelopment precedes photoreceptor nuclear loss in the knockout.
PMID:8638127 SUPPORT PRIMARY RESULT Model organism
"Only a single row of photoreceptor nuclei remained by 3 weeks of age, and the retina was completely devoid of a photoreceptor layer by 8 weeks"
Quantifies the speed of photoreceptor loss in the knockout.
PMID:37363133 SUPPORT PRIMARY RESULT Model organism
"This novel RP model exhibits early onset and rapid rod degeneration, with the vast majority gone by P16."
An independent knockout line reproduces early, rapid rod loss.
+ 1 more reference
Secondary Cone Degeneration and Retinal Remodeling
After rod loss, cones degenerate and the retina remodels: inner retinal neurons lose dendrites, glia activate, deep and intermediate vascular plexus area falls, and the retinal pigment epithelium becomes structurally abnormal. In patients this stage corresponds to extinguished cone responses, bone-spicule pigmentation and, in older children, attenuated retinal vessels.
retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
Animal models
Pde6g CreERT2 knock-in null mouse Mouse recapitulates Cone loss, inner retinal remodeling, vascular degradation and RPE changes after rod loss.
Downstream
Rod-cone dystrophy
Undetectable electroretinogram
Attenuation of retinal blood vessels Retinal vascular degradation follows photoreceptor loss in the Pde6g knockout.
Spicular pigmentation of the retina
Show evidence (2 references)
PMID:37363133 SUPPORT PRIMARY RESULT Model organism
"At P30, rods are gone and few cones remain."
Cone loss follows rod loss in the knockout.
PMID:37363133 SUPPORT PRIMARY RESULT Model organism
"This pathology leads to retinal remodeling, including changes of inner retinal neurons, early activation of glia cells, degradation of retinal vasculature, and structural abnormalities of the RPE."
Describes the remodeling of inner retina, glia, vasculature and RPE that follows photoreceptor loss.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PDE6G-Related Retinopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Cardiovascular 1
Attenuation of retinal blood vessels HP:0007843 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attenuation of retinal blood vessels (HP:0007843). HP:0007843 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"In the younger patients (aged 10 and 12), blood vessels and optic disk were normal, whereas in their older siblings (aged 15 and 16), blood vessel attenuation and pallor of the optic disk were observed."
Age-dependent vessel attenuation in the founder family.
Eye 7
Rod-cone dystrophy HP:0000510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rod-cone dystrophy (HP:0000510), qualified as childhood onset. HP:0000510 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Show evidence (3 references)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"Clinically, the affected individuals described here have severe early-onset RP."
All patients homozygous for the founder allele have severe early-onset retinitis pigmentosa.
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"Both scotopic and photopic electroretinograms (ERGs) were markedly reduced or completely extinct by as early as 4 years of age."
Basis for the childhood onset: rod and cone function is already severely reduced or extinct at 4 years of age.
PMID:39160471 SUPPORT PRIMARY RESULT Human clinical
"Further testing revealed markedly constricted visual fields and electroretinograms showed markedly reduced rod-cone responses"
A compound heterozygous child shows rod-cone pattern dysfunction.
Undetectable electroretinogram HP:0000550 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Undetectable electroretinogram (HP:0000550). HP:0000550 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"Both scotopic and photopic electroretinograms (ERGs) were markedly reduced or completely extinct by as early as 4 years of age."
Rod and cone ERGs are reduced to extinct in early childhood. Not every patient is fully extinct, so the term describes the severe end.
PMID:39160471 SUPPORT PRIMARY RESULT Human clinical
"It is undetectable responses for rod or cones"
The figure legend reports undetectable rod and cone responses in the compound heterozygous child.
Constriction of peripheral visual field HP:0001133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constriction of peripheral visual field (HP:0001133). HP:0001133 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"All patients had markedly constricted visual fields, ranging from 10° to less than 5°, with tiny residual islands of central vision."
Severe field constriction in all patients of the founder family.
PMID:39160471 SUPPORT PRIMARY RESULT Human clinical
"Further testing revealed markedly constricted visual fields"
Field constriction in an unrelated compound heterozygous child.
Spicular pigmentation of the retina HP:0007737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone spicule pigment deposits, annotated with Spicular pigmentation of the retina (HP:0007737). HP:0007737 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"Funduscopic examination revealed relatively mild yet typical bone spicule-type pigment deposits in the periphery and midperiphery."
Fundus finding in the founder family.
PMID:39160471 SUPPORT PRIMARY RESULT Human clinical
"Funduscopic examination revealed typical bone spicule-type pigment deposits in the periphery and midperiphery."
The same fundus finding in an unrelated compound heterozygous child.
Optic disc pallor HP:0000543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic disc pallor (HP:0000543). HP:0000543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"In the younger patients (aged 10 and 12), blood vessels and optic disk were normal, whereas in their older siblings (aged 15 and 16), blood vessel attenuation and pallor of the optic disk were observed."
Optic disc pallor in the older affected siblings.
Cystoid macular edema HP:0011505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cystoid macular edema (HP:0011505). HP:0011505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"Macular involvement in all patients was indicated by the lack of foveal reflex and cystoid macular edema documented by optical coherence tomography (OCT)."
Cystoid macular edema documented by OCT in all affected family members.
Absent foveal reflex HP:0030825 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent foveal reflex (HP:0030825). HP:0030825 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"Macular involvement in all patients was indicated by the lack of foveal reflex and cystoid macular edema documented by optical coherence tomography (OCT)."
Lack of a foveal reflex in all affected family members.
PMID:39160471 SUPPORT PRIMARY RESULT Human clinical
"the optic disk and blood vessels were normal, foveal reflex wasabsent"
Absent foveal reflex in the compound heterozygous child; the source text runs "was" and "absent" together.
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Genetic Associations

1
PDE6G (Causative)
Gene: PDE6G hgnc:8789 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PDE6G (hgnc:8789). hgnc:8789 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"These findings demonstrate the positive role of the γ subunit in maintaining phosphodiesterase activity and confirm the contribution of PDE6G to the etiology of RP in humans."
Gene-discovery paper establishing PDE6G as a human RP gene.
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"In total, we analyzed data from 209 RP and LCA patients, with negative results, indicating that PDE6G mutations are very rare and that their contribution to the overall prevalence of RP and/or LCA in the Israeli population is minor."
Negative screen showing that PDE6G is a very rare cause of RP.
Variants (3)
c.187+1G>T
Intron 3 splice-donor founder variant. In vitro splicing yields a gamma subunit whose last 25 residues are replaced by 52 unrelated residues. Carrier frequency 8.3% in the family's home village, absent from 256 Muslim Israeli controls.
Show evidence (1 reference)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"c.187+1G>T is therefore a founder mutation of village E and is rare in the surrounding Muslim Arab population."
Establishes c.187+1G>T as a local founder allele.
PDE6G exon 3-4 deletion
A homozygous deletion removing PDE6G coding exons 3 and 4 and part of TSPAN10, found in two apparently unrelated patients with autosomal recessive RP in a copy-number screen; the first PDE6G copy-number variant reported in inherited retinal disease.
Show evidence (1 reference)
PMID:28749477 SUPPORT PRIMARY RESULT Human clinical
"In patients P10 and P11 both arrEYE analysis and WES coverage data analysis revealed two apparently identical homozygous deletions of PDE6G"
Identifies the recurrent homozygous PDE6G deletion in two patients.
c.95del p.(Gln32Argfs*62)
Maternally inherited frameshift found in trans with a paternally inherited 6.72 kb 17q25.3 deletion in an 8-year-old Chinese boy.
Show evidence (1 reference)
PMID:39160471 SUPPORT PRIMARY RESULT Human clinical
"The results of genetic testing showed that there was a heterozygous frame shift mutation in the proband’s PDE6G gene, i.e. c.95del: p.Q32Rfs*62, and a deletion of about 6.72Kbp in the proband’s 17q25.317q25.3 segment"
Reports the compound heterozygous genotype.
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Medical Actions

3
Avoidance of PDE5 Inhibitors (Counseling Caution)
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Sildenafil, a PDE5 inhibitor that also acts on retinal PDE6, reversibly and dose-dependently reduced ERG amplitudes in mice heterozygous for the Pde6g null allele but not in wild-type mice. The authors suggest this may be relevant to human RP carriers. There are no human PDE6G data, so this is a counseling caution based on a mouse result, not an established contraindication.
Show evidence (1 reference)
PMID:11157892 SUPPORT PRIMARY RESULT Model organism
"ERGs of the PDEG:(tm1)/+ mice treated with sildenafil showed a reversible, dose-dependent decrease in a- and b-wave amplitudes. Wild-type mice treated with sildenafil did not show significant differences in either a- or b-wave amplitudes compared with untreated control animals."
Heterozygous Pde6g null mice are more sensitive to sildenafil than wild-type mice, the basis for the counseling caution.
Genetic counseling and carrier testing
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Genetic counseling for an autosomal recessive condition. Where a founder allele is common locally, as c.187+1G>T is in the founder family's village, targeted carrier testing is feasible.
Show evidence (1 reference)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"The identification of c.187+1G>T as a common RP-causing mutation in village E will allow for sensitive and cost-effective use of genetic testing for carrier screening and diagnostic purposes."
Supports targeted carrier screening and diagnostic testing for the founder allele.
Carbonic anhydrase inhibition for cystoid macular edema
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: acetazolamide CHEBI:27690 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses acetazolamide (CHEBI:27690). CHEBI:27690 is a therapeutic agent from Chemical Entities of Biological Interest. dorzolamide CHEBI:4702 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dorzolamide (CHEBI:4702). CHEBI:4702 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Oral acetazolamide or topical dorzolamide is the usual first-line treatment for cystoid macular edema in retinitis pigmentosa generally; rebound edema is common with long-term use. Every patient in the PDE6G founder family had cystoid macular edema, but no PDE6G-specific treatment data exist, so this row rests on retinitis pigmentosa systematic reviews.
Mechanism Target:
INHIBITS Cystoid macular edema — Carbonic anhydrase inhibitors reduce central macular thickness in retinitis pigmentosa-associated cystoid macular edema.
Target Phenotypes: Cystoid macular edema HP:0011505 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cystoid macular edema (HP:0011505). HP:0011505 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28987613 SUPPORT REVIEW SYNTHESIS Other
"Oral acetazolamide should be the first-line treatment in CME secondary to retinitis pigmentosa. Topical dorzolamide is an appropriate alternative in patients intolerant to adverse effects of oral acetazolamide."
Systematic review of 23 studies of retinitis pigmentosa-associated CME; not specific to PDE6G.
PMID:35652079 SUPPORT REVIEW SYNTHESIS Other
"Topical CAIs, oral CAIs and local steroids are effective in treating RP-CME. However, due to the overall inferior design and small patient number of the included studies, the quality of evidence was poor."
A later meta-analysis agrees that carbonic anhydrase inhibitors are effective in retinitis pigmentosa CME and grades the evidence as poor.
🔬

Diagnosis

3
Molecular genetic testing
Sequencing of PDE6G (as part of an inherited retinal disease panel, exome, or after homozygosity mapping in a consanguineous family) identifies biallelic variants. Copy-number analysis is also needed: a recurrent homozygous deletion of exons 3-4 and a 6.72 kb deletion have both been reported, and sequencing-based pipelines often miss deletions. Where a founder allele is known, targeted testing serves carrier screening and diagnosis.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic PDE6G loss-of-function variants (splice-site, frameshift, or copy-number deletion) in trans or homozygous.
Show evidence (5 references)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"Sequencing of all coding exons, including exon-intron boundaries, revealed a homozygous single base change (c.187+1G>T) located in the conserved intron 3 donor splice site of PDE6G."
Diagnosis in the founder family came from sequencing PDE6G after homozygosity mapping.
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"The identification of c.187+1G>T as a common RP-causing mutation in village E will allow for sensitive and cost-effective use of genetic testing for carrier screening and diagnostic purposes."
Supports targeted founder-allele testing for diagnosis.
PMID:39160471 SUPPORT PRIMARY RESULT Human clinical
"The patient was given glasses and a whole exome sequencing containing mitochondrial genes was performed."
Exome sequencing identified the compound heterozygous genotype, including a 6.72 kb deletion, in the second family.
+ 2 more references
Full-field electroretinography
Dark-adapted (scotopic) and light-adapted (photopic) full-field ERG documents the severity of rod and cone dysfunction. NCIT has no electroretinography procedure term, so the generic diagnostic procedure term is bound.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: Scotopic and photopic responses markedly reduced or extinguished, as early as 4 years of age; rod-cone pattern.
Show evidence (2 references)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"Both scotopic and photopic electroretinograms (ERGs) were markedly reduced or completely extinct by as early as 4 years of age."
ERG findings in the founder family.
PMID:39160471 SUPPORT PRIMARY RESULT Human clinical
"Further testing revealed markedly constricted visual fields and electroretinograms showed markedly reduced rod-cone responses"
ERG findings in the compound heterozygous child.
Optical coherence tomography
Macular OCT documents cystoid macular edema, present in every affected member of the founder family.
optical coherence tomography NCIT:C20828 NCI Thesaurus (NCIT)
Results: Cystoid macular edema, mild in childhood and severe by mid-adolescence in the founder family.
Show evidence (1 reference)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"Macular involvement in all patients was indicated by the lack of foveal reflex and cystoid macular edema documented by optical coherence tomography (OCT)."
OCT documented cystoid macular edema in all patients of the founder family.
📊

Prevalence

1
Residents of the founder family's home village (village E), northern Israel
Carrier frequency 8300 per 100,000 (3600–15400) >1 in 1,000 (carriers)
c.187+1G>T was found heterozygously in 7 of 84 random adults from the village (8.3%, 95% CI 3.6%-15.4%) and in none of 256 Muslim Israeli controls. This is a local founder figure, not a population prevalence of the disease.
Show evidence (1 reference)
PMID:20655036 SUPPORT PRIMARY RESULT Human clinical
"c.187+1G>T was found heterozygously in 7 of 84 random adults from the same village in which family TB14 resides (village E), thus indicating a carrier frequency of 8.3% (95% confidence interval, 3.6%–15.4%) in this village."
Carrier frequency of the founder allele in the village.
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Animal Models

2
Pde6g tm1 knockout mouse
Targeted null allele of the gamma subunit. Retinal cGMP rises, the catalytic dimer lacks activity, outer segments fail to develop, and photoreceptors are lost by 8 weeks. Used for an allelic series of transgenic Pde6g alleles (Del7C, Y84G, W70A, ILE86TER).
Species
Mouse
Genotype
Pde6g tm1/tm1 (targeted disruption, exon 3 replaced by a neomycin cassette)
Publication
PMID:8638127
Pathograph links
Loss of Rod PDE6 Holoenzyme Catalytic Activity recapitulates fidelity: moderate observes: molecular Catalytic dimer present but without hydrolytic activity.
Limitations: A complete null; the human founder allele produces a C-terminally altered protein, and a later knockout line differs in whether the catalytic subunits are retained.
Show evidence (1 reference)
PMID:8638127 SUPPORT PRIMARY RESULT Model organism
"In homozygous mutant mice, reduced rather than increased PDE activity was apparent; the PDEalphabeta dimer was formed but lacked hydrolytic activity."
Biochemical measurement in the model.
Early-Onset Rod Photoreceptor Degeneration recapitulates fidelity: moderate observes: tissue Photoreceptor layer lost by 8 weeks of age.
Limitations: Mouse retina has no macula, so the cystoid macular edema and foveal findings of patients are not modelled.
Show evidence (1 reference)
PMID:8638127 SUPPORT PRIMARY RESULT Model organism
"Only a single row of photoreceptor nuclei remained by 3 weeks of age, and the retina was completely devoid of a photoreceptor layer by 8 weeks"
Histological time course of degeneration.
Show evidence (1 reference)
PMID:8638127 SUPPORT PRIMARY RESULT Model organism
"A gene-targeting approach was used to disrupt the mouse PDEgamma gene. This mutation resulted in a rapid retinal degeneration resembling human retinitis pigmentosa."
Establishes the knockout as a model of the human disease.
Pde6g CreERT2 knock-in null mouse
A second null line with very early, rapid rod loss (most rods gone by postnatal day 16), cone loss by day 44, and remodeling of inner retinal neurons, glia, vasculature and RPE. PDE6B is also undetectable.
Species
Mouse
Genotype
Pde6g-/- (exons 2 and 3 replaced by CreERT2)
Publication
PMID:37363133
Pathograph links
Secondary Cone Degeneration and Retinal Remodeling recapitulates fidelity: moderate observes: tissue Cone loss, inner retinal remodeling, vascular degradation and RPE changes after rod loss.
Limitations: Mouse degeneration is complete within weeks rather than years, and the mouse retina has no macula.
Show evidence (1 reference)
PMID:37363133 SUPPORT PRIMARY RESULT Model organism
"At P44, all photoreceptors, including cones, have died"
Time course of secondary cone loss in the model.
Show evidence (1 reference)
PMID:37363133 SUPPORT PRIMARY RESULT Model organism
"The pathology in our Pde6g-/- mouse model precisely mirrors human RP progression."
The authors' assessment of the model's fidelity to human RP.
{ }

Source YAML

click to show 
name: PDE6G-Related Retinopathy
creation_date: "2026-10-30T23:00:32Z"
category: Mendelian
description: >-
  PDE6G-related retinopathy (retinitis pigmentosa 57) is a very rare autosomal
  recessive, severe early-onset retinitis pigmentosa caused by biallelic
  loss-of-function variants in PDE6G, which encodes the inhibitory gamma
  subunit of rod cGMP phosphodiesterase 6 (PDE6). Rod PDE6 is a heterotetramer
  of one alpha (PDE6A) and one beta (PDE6B) catalytic subunit and two gamma
  subunits. Although the gamma subunit restrains the catalytic core in the dark,
  its complete absence does not leave PDE6 constitutively active: in knockout
  mice the catalytic dimer lacks hydrolytic activity, retinal cGMP rises, and
  rods degenerate within the first weeks of life, followed by cones. Affected
  people reported to date have extinguished or severely reduced rod and cone
  electroretinograms in early childhood, markedly constricted visual fields,
  bone-spicule pigmentation and cystoid macular edema, with relatively preserved
  central acuity in childhood. Few affected individuals have been described in
  the literature; the founder splice-donor variant c.187+1G>T in one extended
  consanguineous Muslim Arab Israeli family is the best characterized allele.
  There is no disease-specific treatment.
disease_term:
  preferred_term: PDE6G-related retinopathy
  term:
    id: MONDO:1040034
    label: PDE6G-related retinopathy
synonyms:
- Retinitis pigmentosa 57
- RP57
- PDE6G-related retinitis pigmentosa
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0013315
      label: retinitis pigmentosa 57
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO places retinitis pigmentosa 57 (OMIM:613582) as the single child of
      MONDO:1040034. Every reported PDE6G case presents as autosomal recessive
      retinitis pigmentosa, and ClinGen states that RP57 is the only disorder
      currently associated with PDE6G, so the child is captured as a mapping
      rather than a separate has_subtypes row.
notes: >-
  Do not conflate PDE6G with the catalytic subunit genes PDE6A
  (PDE6A-Related_Retinopathy) or PDE6B (the rd1 mouse gene). The three genes
  encode subunits of the same rod holoenzyme, and findings in PDE6A or PDE6B
  models are not used here as PDE6G evidence. PDE6G is also expressed outside
  the retina, but no extraocular phenotype has been found in knockout mice or in
  the first family described. Missense alleles of mouse Pde6g that impair
  inhibition (W70A) cause a stationary night-blindness-like rod defect rather
  than degeneration; no human PDE6G stationary night blindness has been
  reported, so this entry covers the degenerative, retinitis pigmentosa form
  only. Reduced visual acuity (HP:0007663) is not curated as a phenotype: the
  founder-family report describes best-corrected acuity as relatively good
  despite severe field loss, and the compound heterozygous child corrected to
  0.8 in each eye. There is no GeneReviews chapter specific to PDE6G; the Nonsyndromic
  Retinitis Pigmentosa Overview covers the disease class.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals are homozygous or compound heterozygous for PDE6G
    loss-of-function alleles; heterozygous parents are unaffected.
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "revealed a homozygous single base change (c.187+1G>T) located in the conserved intron 3 donor splice site of PDE6G. This mutation cosegregated with the disease in the extended family."
    explanation: >-
      Homozygosity mapping in a consanguineous family and cosegregation of a
      homozygous PDE6G splice variant establish recessive inheritance.
  - reference: PMID:39160471
    reference_title: Analysis of PDE6G mutations in a patient with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Analysis of the parental genes showed that frameshift mutation was inherited from the proband's mother and segment deletion from his father."
    explanation: >-
      Compound heterozygosity with one allele from each unaffected parent in a
      second, unrelated family.
pathophysiology:
- name: PDE6G Loss of Function
  conforms_to: "phototransduction_cascade_dysfunction#Phototransduction Cascade Component Defect"
  biological_scale: MOLECULAR
  description: >-
    Reported human alleles remove or truncate the gamma subunit: the founder
    c.187+1G>T splice-donor variant replaces the last 25 amino acids, which hold
    the overlapping transducin-binding and catalytic-inhibition regions, with
    unrelated sequence; a recurrent multi-kilobase deletion removes coding exons
    3 and 4; and a frameshift (c.95del) truncates the protein early. ClinGen
    concludes that the disease mechanism is loss of function. The molecular
    function bound here is the gamma subunit's own activity as an inhibitor of
    the PDE6 catalytic core (GO enzyme inhibitor activity, the term GO
    annotates to PDE6G); its loss paradoxically lowers rather than raises PDE6
    activity, as the next node records.
  gene:
    preferred_term: PDE6G
    modifier: DECREASED
    term:
      id: hgnc:8789
      label: PDE6G
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  molecular_functions:
  - preferred_term: PDE6 catalytic subunit inhibitor activity
    modifier: DECREASED
    term:
      id: GO:0004857
      label: enzyme inhibitor activity
  downstream:
  - target: Loss of Rod PDE6 Holoenzyme Catalytic Activity
    description: >-
      Without a functional gamma subunit, the rod PDE6 catalytic dimer is
      present in the Pde6g knockout but does not hydrolyze cGMP.
    evidence:
    - reference: PMID:8638127
      reference_title: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In homozygous mutant mice, reduced rather than increased PDE activity was apparent; the PDEalphabeta dimer was formed but lacked hydrolytic activity."
      explanation: >-
        Directly links absence of the gamma subunit to loss of catalytic
        activity of the remaining PDE6 alpha-beta dimer.
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "We used an in vitro splicing assay to demonstrate that this mutation leads to incorrect splicing."
    explanation: >-
      A minigene splicing assay shows that the founder c.187+1G>T variant
      disrupts normal PDE6G splicing.
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "the splicing product obtained from the c.187+1G>T mutant allele encodes for an abnormal Pγ protein in which the last 25 amino acids (D63-I87) are replaced by 52 irrelevant amino acids. The missing amino acids include the overlapping regions responsible for transducin binding and Pαβ inhibition."
    explanation: >-
      Defines the predicted protein consequence of the founder allele: loss of
      the C-terminal functional domains of the gamma subunit.
  - reference: CGGV:assertion_b5b69965-33e0-4a8c-b5dd-faede6c39912-2024-06-06T160000.000Z
    reference_title: "PDE6G / PDE6G-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The disease mechanism appears to be loss of function."
    explanation: >-
      ClinGen Retina expert panel summary of the gene-disease mechanism.
- name: Loss of Rod PDE6 Holoenzyme Catalytic Activity
  biological_scale: MOLECULAR
  description: >-
    The gamma subunit is required not only to inhibit the catalytic core in the
    dark but also, through its C terminus, for a stable, active holoenzyme. Its
    absence or C-terminal truncation leaves little or no light-regulated cGMP
    hydrolysis. Mouse models disagree on whether the catalytic subunits
    themselves are lost: the original neomycin-insertion knockout kept a
    PDE6A/PDE6B dimer that lacked activity, whereas a later exon 2-3 knockout
    and the C-terminal deletion allele lost most PDE6B or PDE6A/PDE6B protein.
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  molecular_functions:
  - preferred_term: 3',5'-cyclic-GMP phosphodiesterase activity
    modifier: DECREASED
    term:
      id: GO:0047555
      label: 3',5'-cyclic-GMP phosphodiesterase activity
  downstream:
  - target: Rod Outer-Segment cGMP Accumulation
    description: >-
      Loss of PDE6 activity prevents light from lowering cGMP, and cGMP rises
      before photoreceptors are lost.
    evidence:
    - reference: PMID:8638127
      reference_title: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In contrast to wild-type mice, light did not reduce retinal cGMP levels in the Pdegtml/Pdegtml mice."
      explanation: >-
        Shows that without the gamma subunit light no longer drives cGMP
        hydrolysis in the retina.
  evidence:
  - reference: PMID:8638127
    reference_title: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Thus, the inhibitory gamma subunit appears to be necessary for integrity of the photoreceptors and expression of PDE activity in vivo."
    explanation: >-
      The knockout study's conclusion that PDE6 activity in vivo requires the
      gamma subunit.
  - reference: PMID:11853759
    reference_title: The positive role of the carboxyl terminus of the gamma subunit of retinal cGMP-phosphodiesterase in maintaining phosphodiesterase activity in vivo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Instead, our results showed that the Del7C transgene could not complement the Pdeg(tm1)/Pdeg(tm1) mutant for photoreceptor survival. In fact, animals carrying the Del7C transgene have low PDE activity as well as reduced PDEalpha and PDEbeta content."
    explanation: >-
      A gamma subunit lacking its last seven residues fails to rescue the
      knockout and leaves low PDE activity with reduced catalytic subunits,
      which is the class of defect the human founder allele (C-terminal
      replacement) is predicted to cause.
  - reference: PMID:37363133
    reference_title: A New Preclinical Model of Retinitis Pigmentosa Due to Pde6g Deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "we immunolabeled sections for PDE6B and found that, like PDE6G, PDE6B immunolabeling was not detectable in Pde6g−/− retinas"
    explanation: >-
      In the exon 2-3 knockout the PDE6B catalytic subunit is also lost from
      rod outer segments.
  - reference: PMID:27268253
    reference_title: Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Our data demonstrate that AIPL1 is an obligatory chaperone for PDE6, whereas Pγ acts as potent co-chaperone that markedly enhances production of the folded enzyme provided that AIPL1 is present."
    explanation: >-
      A heterologous expression system (using the cone PDE6C catalytic subunit)
      shows that the gamma subunit acts as a co-chaperone for folding of
      functional PDE6. It supports a role in holoenzyme production only by
      extrapolation to the rod enzyme.
- name: Rod Outer-Segment cGMP Accumulation
  conforms_to: "phototransduction_cascade_dysfunction#Loss of Outer-Segment cGMP and Calcium Set-Point Control"
  biological_scale: CELLULAR
  description: >-
    Retinal cGMP is elevated in Pde6g knockout mice and the rise precedes
    photoreceptor degeneration. The proposed consequence is that cGMP-gated
    cation channels stay open, imposing a sustained ion and energy load on
    rods. That last step is the authors' hypothesis rather than a measurement.
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  downstream:
  - target: Early-Onset Rod Photoreceptor Degeneration
    description: >-
      Persistently high cGMP is proposed to keep cGMP-gated channels open and
      overload rods, resulting in their degeneration.
    evidence:
    - reference: PMID:8638127
      reference_title: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "The high cGMP concentrations may keep cGMP-gated cationic channels open continuously and lead to an excessive energy load on the rod photoreceptors, resulting in degeneration."
      explanation: >-
        The knockout study's proposed mechanism linking elevated cGMP to rod
        degeneration; stated as a hypothesis, so the edge is indirect.
  evidence:
  - reference: PMID:8638127
    reference_title: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Moreover, the increase in cGMP levels preceded photoreceptor degeneration"
    explanation: >-
      Shows cGMP elevation in the knockout retina before photoreceptor loss,
      placing it upstream of degeneration.
- name: Early-Onset Rod Photoreceptor Degeneration
  conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
  biological_scale: CELLULAR
  description: >-
    Rod outer segments fail to develop normally and rods are lost within the
    first two to three postnatal weeks in Pde6g knockout mice. In patients,
    rod-driven electroretinogram responses are already extinguished or severely
    reduced by about 4 years of age, matching the severe early-onset course.
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: photoreceptor cell outer segment organization
    modifier: DECREASED
    term:
      id: GO:0035845
      label: photoreceptor cell outer segment organization
  downstream:
  - target: Secondary Cone Degeneration and Retinal Remodeling
    description: >-
      Cone loss follows rod loss, and rod loss drives remodeling of inner
      retinal neurons, glia, vasculature and retinal pigment epithelium.
    evidence:
    - reference: PMID:37363133
      reference_title: A New Preclinical Model of Retinitis Pigmentosa Due to Pde6g Deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Thus, the loss of PDE6G leads to rapid degeneration of rod photoreceptor cells and secondary degeneration of cones"
      explanation: >-
        Orders rod degeneration before, and as the cause of, cone degeneration
        in the Pde6g knockout.
  - target: Constriction of peripheral visual field
  evidence:
  - reference: PMID:8638127
    reference_title: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Transmission electron microscopy revealed that the photoreceptor outer segments had failed to develop normally and were disorganized at postnatal day 10 (P10), and that most of the outer segments were lost by P13, although the photoreceptor nuclear layer remained intact"
    explanation: >-
      Outer segment maldevelopment precedes photoreceptor nuclear loss in the
      knockout.
  - reference: PMID:8638127
    reference_title: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Only a single row of photoreceptor nuclei remained by 3 weeks of age, and the retina was completely devoid of a photoreceptor layer by 8 weeks"
    explanation: >-
      Quantifies the speed of photoreceptor loss in the knockout.
  - reference: PMID:37363133
    reference_title: A New Preclinical Model of Retinitis Pigmentosa Due to Pde6g Deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "This novel RP model exhibits early onset and rapid rod degeneration, with the vast majority gone by P16."
    explanation: >-
      An independent knockout line reproduces early, rapid rod loss.
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Both scotopic and photopic electroretinograms (ERGs) were markedly reduced or completely extinct by as early as 4 years of age."
    explanation: >-
      Early loss of rod (scotopic) function in patients homozygous for the
      founder allele.
- name: Secondary Cone Degeneration and Retinal Remodeling
  conforms_to: "photoreceptor_degeneration#Secondary Cone Degeneration and Outer Retinal Thinning"
  biological_scale: TISSUE
  description: >-
    After rod loss, cones degenerate and the retina remodels: inner retinal
    neurons lose dendrites, glia activate, deep and intermediate vascular plexus
    area falls, and the retinal pigment epithelium becomes structurally
    abnormal. In patients this stage corresponds to extinguished cone
    responses, bone-spicule pigmentation and, in older children, attenuated
    retinal vessels.
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  downstream:
  - target: Rod-cone dystrophy
  - target: Undetectable electroretinogram
  - target: Attenuation of retinal blood vessels
    description: >-
      Retinal vascular degradation follows photoreceptor loss in the Pde6g
      knockout.
    evidence:
    - reference: PMID:37363133
      reference_title: A New Preclinical Model of Retinitis Pigmentosa Due to Pde6g Deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "This pathology leads to retinal remodeling, including changes of inner retinal neurons, early activation of glia cells, degradation of retinal vasculature, and structural abnormalities of the RPE."
      explanation: >-
        States that photoreceptor degeneration leads to degradation of the
        retinal vasculature in the knockout.
  - target: Spicular pigmentation of the retina
  evidence:
  - reference: PMID:37363133
    reference_title: A New Preclinical Model of Retinitis Pigmentosa Due to Pde6g Deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "At P30, rods are gone and few cones remain."
    explanation: >-
      Cone loss follows rod loss in the knockout.
  - reference: PMID:37363133
    reference_title: A New Preclinical Model of Retinitis Pigmentosa Due to Pde6g Deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "This pathology leads to retinal remodeling, including changes of inner retinal neurons, early activation of glia cells, degradation of retinal vasculature, and structural abnormalities of the RPE."
    explanation: >-
      Describes the remodeling of inner retina, glia, vasculature and RPE that
      follows photoreceptor loss.
phenotypes:
- category: Ophthalmological
  name: Rod-cone dystrophy
  description: >-
    Severe early-onset retinitis pigmentosa with rod-predominant, then
    generalized, photoreceptor dysfunction.
  phenotype_term:
    preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Clinically, the affected individuals described here have severe early-onset RP."
    explanation: >-
      All patients homozygous for the founder allele have severe early-onset
      retinitis pigmentosa.
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Both scotopic and photopic electroretinograms (ERGs) were markedly reduced or completely extinct by as early as 4 years of age."
    explanation: >-
      Basis for the childhood onset: rod and cone function is already severely
      reduced or extinct at 4 years of age.
  - reference: PMID:39160471
    reference_title: Analysis of PDE6G mutations in a patient with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Further testing revealed markedly constricted visual fields and electroretinograms showed markedly reduced rod-cone responses"
    explanation: >-
      A compound heterozygous child shows rod-cone pattern dysfunction.
- category: Ophthalmological
  name: Undetectable electroretinogram
  description: >-
    Scotopic and photopic full-field electroretinograms are markedly reduced or
    extinguished, by as early as 4 years of age in the founder family.
  phenotype_term:
    preferred_term: Undetectable electroretinogram
    term:
      id: HP:0000550
      label: Undetectable electroretinogram
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Both scotopic and photopic electroretinograms (ERGs) were markedly reduced or completely extinct by as early as 4 years of age."
    explanation: >-
      Rod and cone ERGs are reduced to extinct in early childhood. Not every
      patient is fully extinct, so the term describes the severe end.
  - reference: PMID:39160471
    reference_title: Analysis of PDE6G mutations in a patient with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "It is undetectable responses for rod or cones"
    explanation: >-
      The figure legend reports undetectable rod and cone responses in the
      compound heterozygous child.
- category: Ophthalmological
  name: Constriction of peripheral visual field
  description: >-
    Visual fields are markedly constricted, to 10 degrees or less, with small
    residual islands of central vision.
  phenotype_term:
    preferred_term: Constriction of peripheral visual field
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "All patients had markedly constricted visual fields, ranging from 10° to less than 5°, with tiny residual islands of central vision."
    explanation: >-
      Severe field constriction in all patients of the founder family.
  - reference: PMID:39160471
    reference_title: Analysis of PDE6G mutations in a patient with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Further testing revealed markedly constricted visual fields"
    explanation: >-
      Field constriction in an unrelated compound heterozygous child.
- category: Ophthalmological
  name: Spicular pigmentation of the retina
  description: >-
    Typical bone-spicule pigment deposits, relatively mild in childhood, in the
    retinal periphery and midperiphery.
  phenotype_term:
    preferred_term: Bone spicule pigment deposits
    term:
      id: HP:0007737
      label: Spicular pigmentation of the retina
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Funduscopic examination revealed relatively mild yet typical bone spicule-type pigment deposits in the periphery and midperiphery."
    explanation: >-
      Fundus finding in the founder family.
  - reference: PMID:39160471
    reference_title: Analysis of PDE6G mutations in a patient with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Funduscopic examination revealed typical bone spicule-type pigment deposits in the periphery and midperiphery."
    explanation: >-
      The same fundus finding in an unrelated compound heterozygous child.
- category: Ophthalmological
  name: Attenuation of retinal blood vessels
  description: >-
    Retinal vessels were normal in the younger patients (10 and 12 years) and
    attenuated in their older siblings (15 and 16 years) in the founder family.
  phenotype_term:
    preferred_term: Attenuation of retinal blood vessels
    term:
      id: HP:0007843
      label: Attenuation of retinal blood vessels
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In the younger patients (aged 10 and 12), blood vessels and optic disk were normal, whereas in their older siblings (aged 15 and 16), blood vessel attenuation and pallor of the optic disk were observed."
    explanation: >-
      Age-dependent vessel attenuation in the founder family.
- category: Ophthalmological
  name: Optic disc pallor
  description: >-
    Optic disc pallor appears in adolescence in the founder family; it was
    absent in the younger affected siblings.
  phenotype_term:
    preferred_term: Optic disc pallor
    term:
      id: HP:0000543
      label: Optic disc pallor
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In the younger patients (aged 10 and 12), blood vessels and optic disk were normal, whereas in their older siblings (aged 15 and 16), blood vessel attenuation and pallor of the optic disk were observed."
    explanation: >-
      Optic disc pallor in the older affected siblings.
- category: Ophthalmological
  name: Cystoid macular edema
  description: >-
    Macular involvement, with cystoid macular edema on optical coherence
    tomography, was present in all patients of the founder family, ranging from
    mild at age 10 to severe at age 16.
  phenotype_term:
    preferred_term: Cystoid macular edema
    term:
      id: HP:0011505
      label: Cystoid macular edema
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Macular involvement in all patients was indicated by the lack of foveal reflex and cystoid macular edema documented by optical coherence tomography (OCT)."
    explanation: >-
      Cystoid macular edema documented by OCT in all affected family members.
- category: Ophthalmological
  name: Absent foveal reflex
  description: >-
    The foveal reflex is absent in the founder family and in the compound
    heterozygous child.
  phenotype_term:
    preferred_term: Absent foveal reflex
    term:
      id: HP:0030825
      label: Absent foveal reflex
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Macular involvement in all patients was indicated by the lack of foveal reflex and cystoid macular edema documented by optical coherence tomography (OCT)."
    explanation: >-
      Lack of a foveal reflex in all affected family members.
  - reference: PMID:39160471
    reference_title: Analysis of PDE6G mutations in a patient with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "the optic disk and blood vessels were normal, foveal reflex wasabsent"
    explanation: >-
      Absent foveal reflex in the compound heterozygous child; the source text
      runs "was" and "absent" together.
genetic:
- name: PDE6G
  gene_term:
    preferred_term: PDE6G
    term:
      id: hgnc:8789
      label: PDE6G
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Causative
  features: >-
    Reported alleles are loss of function: the founder splice-donor variant
    c.187+1G>T (homozygous in an extended Muslim Arab Israeli family), a
    recurrent deletion removing coding exons 3 and 4 of PDE6G together with
    part of the neighbouring TSPAN10 gene (homozygous in two apparently
    unrelated patients), and a frameshift c.95del p.(Gln32Argfs*62) in trans
    with a 6.72 kb 17q25.3 deletion in a Chinese child. ClinGen also notes
    unpublished homozygous c.69dup p.(Arg24GlnfsTer6) cases. PDE6G is a very
    rare cause of RP: screens of 209 Israeli and 704 other retinal-degeneration
    patients found no further mutations.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_b5b69965-33e0-4a8c-b5dd-faede6c39912-2024-06-06T160000.000Z
    evidence:
    - reference: CGGV:assertion_b5b69965-33e0-4a8c-b5dd-faede6c39912-2024-06-06T160000.000Z
      reference_title: "PDE6G / PDE6G-related retinopathy (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PDE6G | HGNC:8789 | PDE6G-related retinopathy | MONDO:1040034 | AR | Definitive"
      explanation: >-
        ClinGen Retina expert panel classifies PDE6G-related retinopathy (AR)
        as Definitive.
  variants:
  - name: c.187+1G>T
    description: >-
      Intron 3 splice-donor founder variant. In vitro splicing yields a gamma
      subunit whose last 25 residues are replaced by 52 unrelated residues.
      Carrier frequency 8.3% in the family's home village, absent from 256
      Muslim Israeli controls.
    evidence:
    - reference: PMID:20655036
      reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "c.187+1G>T is therefore a founder mutation of village E and is rare in the surrounding Muslim Arab population."
      explanation: >-
        Establishes c.187+1G>T as a local founder allele.
  - name: PDE6G exon 3-4 deletion
    description: >-
      A homozygous deletion removing PDE6G coding exons 3 and 4 and part of
      TSPAN10, found in two apparently unrelated patients with autosomal
      recessive RP in a copy-number screen; the first PDE6G copy-number variant
      reported in inherited retinal disease.
    evidence:
    - reference: PMID:28749477
      reference_title: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "In patients P10 and P11 both arrEYE analysis and WES coverage data analysis revealed two apparently identical homozygous deletions of PDE6G"
      explanation: >-
        Identifies the recurrent homozygous PDE6G deletion in two patients.
  - name: c.95del p.(Gln32Argfs*62)
    description: >-
      Maternally inherited frameshift found in trans with a paternally
      inherited 6.72 kb 17q25.3 deletion in an 8-year-old Chinese boy.
    evidence:
    - reference: PMID:39160471
      reference_title: Analysis of PDE6G mutations in a patient with retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "The results of genetic testing showed that there was a heterozygous frame shift mutation in the proband’s PDE6G gene, i.e. c.95del: p.Q32Rfs*62, and a deletion of about 6.72Kbp in the proband’s 17q25.317q25.3 segment"
      explanation: >-
        Reports the compound heterozygous genotype.
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "These findings demonstrate the positive role of the γ subunit in maintaining phosphodiesterase activity and confirm the contribution of PDE6G to the etiology of RP in humans."
    explanation: >-
      Gene-discovery paper establishing PDE6G as a human RP gene.
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In total, we analyzed data from 209 RP and LCA patients, with negative results, indicating that PDE6G mutations are very rare and that their contribution to the overall prevalence of RP and/or LCA in the Israeli population is minor."
    explanation: >-
      Negative screen showing that PDE6G is a very rare cause of RP.
treatments:
- name: Avoidance of PDE5 Inhibitors (Counseling Caution)
  therapeutic_modality: OTHER
  description: >-
    Sildenafil, a PDE5 inhibitor that also acts on retinal PDE6, reversibly
    and dose-dependently reduced ERG amplitudes in mice heterozygous for the
    Pde6g null allele but not in wild-type mice. The authors suggest this may be
    relevant to human RP carriers. There are no human PDE6G data, so this is a
    counseling caution based on a mouse result, not an established
    contraindication.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:11157892
    reference_title: Sildenafil-mediated reduction in retinal function in heterozygous mice lacking the gamma-subunit of phosphodiesterase.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "ERGs of the PDEG:(tm1)/+ mice treated with sildenafil showed a reversible, dose-dependent decrease in a- and b-wave amplitudes. Wild-type mice treated with sildenafil did not show significant differences in either a- or b-wave amplitudes compared with untreated control animals."
    explanation: >-
      Heterozygous Pde6g null mice are more sensitive to sildenafil than
      wild-type mice, the basis for the counseling caution.
- name: Genetic counseling and carrier testing
  therapeutic_modality: OTHER
  description: >-
    Genetic counseling for an autosomal recessive condition. Where a founder
    allele is common locally, as c.187+1G>T is in the founder family's village,
    targeted carrier testing is feasible.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The identification of c.187+1G>T as a common RP-causing mutation in village E will allow for sensitive and cost-effective use of genetic testing for carrier screening and diagnostic purposes."
    explanation: >-
      Supports targeted carrier screening and diagnostic testing for the
      founder allele.
- name: Carbonic anhydrase inhibition for cystoid macular edema
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Oral acetazolamide or topical dorzolamide is the usual first-line treatment
    for cystoid macular edema in retinitis pigmentosa generally; rebound edema
    is common with long-term use. Every patient in the PDE6G founder family had
    cystoid macular edema, but no PDE6G-specific treatment data exist, so this
    row rests on retinitis pigmentosa systematic reviews.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acetazolamide
      term:
        id: CHEBI:27690
        label: acetazolamide
    - preferred_term: dorzolamide
      term:
        id: CHEBI:4702
        label: dorzolamide
  target_phenotypes:
  - preferred_term: Cystoid macular edema
    term:
      id: HP:0011505
      label: Cystoid macular edema
  target_mechanisms:
  - target: Cystoid macular edema
    treatment_effect: INHIBITS
    description: >-
      Carbonic anhydrase inhibitors reduce central macular thickness in
      retinitis pigmentosa-associated cystoid macular edema.
  evidence:
  - reference: PMID:28987613
    reference_title: "Treatment of cystoid macular edema secondary to retinitis pigmentosa: a systematic review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Oral acetazolamide should be the first-line treatment in CME secondary to retinitis pigmentosa. Topical dorzolamide is an appropriate alternative in patients intolerant to adverse effects of oral acetazolamide."
    explanation: >-
      Systematic review of 23 studies of retinitis pigmentosa-associated CME;
      not specific to PDE6G.
  - reference: PMID:35652079
    reference_title: "Management of Cystoid Macular Edema in Retinitis Pigmentosa: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Topical CAIs, oral CAIs and local steroids are effective in treating RP-CME. However, due to the overall inferior design and small patient number of the included studies, the quality of evidence was poor."
    explanation: >-
      A later meta-analysis agrees that carbonic anhydrase inhibitors are
      effective in retinitis pigmentosa CME and grades the evidence as poor.
diagnosis:
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Sequencing of PDE6G (as part of an inherited retinal disease panel, exome,
    or after homozygosity mapping in a consanguineous family) identifies
    biallelic variants. Copy-number analysis is also needed: a recurrent
    homozygous deletion of exons 3-4 and a 6.72 kb deletion have both been
    reported, and sequencing-based pipelines often miss deletions. Where a
    founder allele is known, targeted testing serves carrier screening and
    diagnosis.
  results: >-
    Biallelic PDE6G loss-of-function variants (splice-site, frameshift, or
    copy-number deletion) in trans or homozygous.
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Sequencing of all coding exons, including exon-intron boundaries, revealed a homozygous single base change (c.187+1G>T) located in the conserved intron 3 donor splice site of PDE6G."
    explanation: >-
      Diagnosis in the founder family came from sequencing PDE6G after
      homozygosity mapping.
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The identification of c.187+1G>T as a common RP-causing mutation in village E will allow for sensitive and cost-effective use of genetic testing for carrier screening and diagnostic purposes."
    explanation: >-
      Supports targeted founder-allele testing for diagnosis.
  - reference: PMID:39160471
    reference_title: Analysis of PDE6G mutations in a patient with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The patient was given glasses and a whole exome sequencing containing mitochondrial genes was performed."
    explanation: >-
      Exome sequencing identified the compound heterozygous genotype,
      including a 6.72 kb deletion, in the second family.
  - reference: PMID:28749477
    reference_title: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In patients P10 and P11 both arrEYE analysis and WES coverage data analysis revealed two apparently identical homozygous deletions of PDE6G"
    explanation: >-
      The exon 3-4 deletion was detected by targeted CNV array and exome
      coverage analysis, not by variant calling.
  - reference: PMID:28749477
    reference_title: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "most NGS studies still fail to detect them, leading to an underestimation of CNVs as underlying cause of IRD."
    explanation: >-
      States that next-generation sequencing studies usually miss
      copy-number variants in inherited retinal disease, the reason a
      dedicated CNV analysis is listed here.
- name: Full-field electroretinography
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Dark-adapted (scotopic) and light-adapted (photopic) full-field ERG
    documents the severity of rod and cone dysfunction. NCIT has no
    electroretinography procedure term, so the generic diagnostic procedure
    term is bound.
  results: >-
    Scotopic and photopic responses markedly reduced or extinguished, as early
    as 4 years of age; rod-cone pattern.
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Both scotopic and photopic electroretinograms (ERGs) were markedly reduced or completely extinct by as early as 4 years of age."
    explanation: >-
      ERG findings in the founder family.
  - reference: PMID:39160471
    reference_title: Analysis of PDE6G mutations in a patient with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Further testing revealed markedly constricted visual fields and electroretinograms showed markedly reduced rod-cone responses"
    explanation: >-
      ERG findings in the compound heterozygous child.
- name: Optical coherence tomography
  diagnosis_term:
    preferred_term: optical coherence tomography
    term:
      id: NCIT:C20828
      label: Optical Coherence Tomography
  description: >-
    Macular OCT documents cystoid macular edema, present in every affected
    member of the founder family.
  results: >-
    Cystoid macular edema, mild in childhood and severe by mid-adolescence in
    the founder family.
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Macular involvement in all patients was indicated by the lack of foveal reflex and cystoid macular edema documented by optical coherence tomography (OCT)."
    explanation: >-
      OCT documented cystoid macular edema in all patients of the founder
      family.
prevalence:
- population: Residents of the founder family's home village (village E), northern Israel
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 8300
  rate_low: 3600
  rate_high: 15400
  notes: >-
    c.187+1G>T was found heterozygously in 7 of 84 random adults from the
    village (8.3%, 95% CI 3.6%-15.4%) and in none of 256 Muslim Israeli
    controls. This is a local founder figure, not a population prevalence of
    the disease.
  evidence:
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "c.187+1G>T was found heterozygously in 7 of 84 random adults from the same village in which family TB14 resides (village E), thus indicating a carrier frequency of 8.3% (95% confidence interval, 3.6%–15.4%) in this village."
    explanation: >-
      Carrier frequency of the founder allele in the village.
animal_models:
- name: Pde6g tm1 knockout mouse
  species: Mouse
  genotype: Pde6g tm1/tm1 (targeted disruption, exon 3 replaced by a neomycin cassette)
  publication: PMID:8638127
  description: >-
    Targeted null allele of the gamma subunit. Retinal cGMP rises, the
    catalytic dimer lacks activity, outer segments fail to develop, and
    photoreceptors are lost by 8 weeks. Used for an allelic series of
    transgenic Pde6g alleles (Del7C, Y84G, W70A, ILE86TER).
  evidence:
  - reference: PMID:8638127
    reference_title: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "A gene-targeting approach was used to disrupt the mouse PDEgamma gene. This mutation resulted in a rapid retinal degeneration resembling human retinitis pigmentosa."
    explanation: >-
      Establishes the knockout as a model of the human disease.
  modeled_mechanisms:
  - target: Loss of Rod PDE6 Holoenzyme Catalytic Activity
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Catalytic dimer present but without hydrolytic activity.
    limitations: >-
      A complete null; the human founder allele produces a C-terminally altered
      protein, and a later knockout line differs in whether the catalytic
      subunits are retained.
    evidence:
    - reference: PMID:8638127
      reference_title: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In homozygous mutant mice, reduced rather than increased PDE activity was apparent; the PDEalphabeta dimer was formed but lacked hydrolytic activity."
      explanation: Biochemical measurement in the model.
  - target: Early-Onset Rod Photoreceptor Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Photoreceptor layer lost by 8 weeks of age.
    limitations: >-
      Mouse retina has no macula, so the cystoid macular edema and foveal
      findings of patients are not modelled.
    evidence:
    - reference: PMID:8638127
      reference_title: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Only a single row of photoreceptor nuclei remained by 3 weeks of age, and the retina was completely devoid of a photoreceptor layer by 8 weeks"
      explanation: Histological time course of degeneration.
- name: Pde6g CreERT2 knock-in null mouse
  species: Mouse
  genotype: Pde6g-/- (exons 2 and 3 replaced by CreERT2)
  publication: PMID:37363133
  description: >-
    A second null line with very early, rapid rod loss (most rods gone by
    postnatal day 16), cone loss by day 44, and remodeling of inner retinal
    neurons, glia, vasculature and RPE. PDE6B is also undetectable.
  evidence:
  - reference: PMID:37363133
    reference_title: A New Preclinical Model of Retinitis Pigmentosa Due to Pde6g Deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "The pathology in our Pde6g-/- mouse model precisely mirrors human RP progression."
    explanation: >-
      The authors' assessment of the model's fidelity to human RP.
  modeled_mechanisms:
  - target: Secondary Cone Degeneration and Retinal Remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Cone loss, inner retinal remodeling, vascular degradation and RPE changes after rod loss.
    limitations: >-
      Mouse degeneration is complete within weeks rather than years, and the
      mouse retina has no macula.
    evidence:
    - reference: PMID:37363133
      reference_title: A New Preclinical Model of Retinitis Pigmentosa Due to Pde6g Deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "At P44, all photoreceptors, including cones, have died"
      explanation: Time course of secondary cone loss in the model.
discussions:
- discussion_id: pde6g_catalytic_subunit_stability
  prompt: >-
    Does loss of the PDE6 gamma subunit leave an inactive but stable catalytic
    dimer, or does it destabilize the PDE6A/PDE6B subunits themselves, and which
    applies to the human alleles?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of Rod PDE6 Holoenzyme Catalytic Activity
  rationale: >-
    The two null mouse lines differ: the original neomycin-insertion knockout
    retained a PDE6A/PDE6B dimer without activity, while the exon 2-3 knockout
    and the C-terminal Del7C allele lost most catalytic protein. The answer
    decides whether residual catalytic subunit is present for a gene
    supplementation approach to work with, and no human tissue or patient-derived
    retinal model has been studied.
  evidence:
  - reference: PMID:37363133
    reference_title: A New Preclinical Model of Retinitis Pigmentosa Due to Pde6g Deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Interestingly, the Pde6gtm1/tm1 mouse line, in which the third exon was replaced with the bacterial neomycin resistance gene, shows a slightly later disease onset, a similarly rapid rate of photoreceptor degeneration (1 row of cone photoreceptors remaining at P21), and assembly, folding, and stability of the PDE6A/PDE6B complex does not appear to be affected."
    explanation: >-
      The later model's authors state the discrepancy with the original
      knockout directly.
- discussion_id: pde6g_stationary_night_blindness_alleles
  prompt: >-
    Can human PDE6G missense alleles that weaken inhibition without abolishing
    the protein cause congenital stationary night blindness instead of
    retinitis pigmentosa, as some mouse alleles do?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - disease#PDE6G-Related Retinopathy
  rationale: >-
    An allelic series in mice spans stationary night blindness to progressive
    degeneration, and the gene-discovery authors anticipated that other human
    alleles might cause stationary night blindness. All reported human alleles
    are loss of function and cause RP, so the allelic spectrum in humans is
    untested.
  evidence:
  - reference: PMID:12700134
    reference_title: Stationary night blindness or progressive retinal degeneration in mice carrying different alleles of PDE gamma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "we have been studying an allelic series of mutations in the gamma-subunit of the cGMP phosphodiesterase gene (Pdeg) that resulted in visual defects ranging from stationary night blindness to progressive retinal degeneration."
    explanation: >-
      Mouse Pde6g alleles produce either stationary or degenerative disease.
  - reference: PMID:20655036
    reference_title: Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Nevertheless, it is possible that different mutant alleles of PDE6G will be discovered in the future in patients with CSNB."
    explanation: >-
      The gene-discovery authors raise the possibility of a human stationary
      night blindness allele.
references:
- reference: PMID:20301590
  title: Nonsyndromic Retinitis Pigmentosa Overview.
  tags:
  - GeneReviews
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: NEUROLOGIC
📚

References & Deep Research

References

1
PMID:20301590
Nonsyndromic Retinitis Pigmentosa Overview.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: PDE6G-Related Retinopathy · 2026-10-30T23:51:12Z · View source

New entry for PDE6G-related retinopathy (MONDO:1040034), entry_type DISEASE. MONDO's only child, retinitis pigmentosa 57 (MONDO:0013315), is the same disease and is recorded as a skos:narrowMatch mapping plus synonyms rather than a has_subtypes row, following CNGA1-Related_Retinopathy. Deep research: one OpenScientist report (no fallback); 12/12 references resolved, 0 unresolved terms. Errors found in it: it gives PDE6G as HGNC:8788, which is PDE6D (flagged by preflight-dr), and its suggested NCIT treatment codes name unrelated concepts (C15431 is Hematopoietic Cell Transplantation, C15277 Mastectomy, C15917 Arterial Embolization). It frames the mechanism as loss of inhibitory control with excess PDE6 activity and does not cite the Pde6g null mouse (PMID:8638127), in which PDE6 activity is reduced and cGMP rises; the entry follows the knockout data. It also missed the second and third published families (PMID:28749477 exon 3-4 deletion; PMID:39160471 compound heterozygous child), found here by PubMed search and in the ClinGen Definitive assertion summary. Its Pde6b gene-therapy rescue papers (PMID:29721933, PMID:35195763) were not used because they are PDE6B, not PDE6G. Reduced visual acuity, listed in the HPO annotation set, was left out because the source describes acuity as relatively good. Validated with just validate, count-verified-snippets (52/52), validate-terms, check-entity-refs, check-causal-targets, check-gene-validity, check-snippet-grading/length, check-title-snippets, check-reference-titles, list-gene-term-mismatches, check-genereviews and validate-disorders, all passing. CI round: the PR's test (3.13) job failed two whole-repo gates. find_missing_reference_titles flagged the two ClinGen (CGGV) evidence items, which lacked reference_title; filled from the cache frontmatter with scripts/backfill_reference_titles.py. check_gene_activity_grounding flagged PDE6G on the PDE6G Loss of Function node, which bound no molecular function; bound GO:0004857 enzyme inhibitor activity (DECREASED), the molecular function GO annotates to PDE6G (QuickGO, P18545), label checked through ols:go. Both gates, check_folded_hyphens and validate-disorders pass after the change. Review round 1: added a diagnosis section (molecular genetic testing bound to NCIT:C15709 Genetic Testing, including copy-number analysis for the PDE6G deletions, quoted from PMID:20655036, PMID:39160471 and PMID:28749477; full-field ERG bound to NCIT:C18020 because an OLS search of NCIT found no electroretinography procedure term; optical coherence tomography bound to NCIT:C20828). Added a carbonic anhydrase inhibitor treatment for cystoid macular edema sourced from two retinitis pigmentosa systematic reviews (PMID:28987613, PMID:35652079), linked to the Cystoid macular edema phenotype. Changed the rod degeneration node's biological_scale to CELLULAR and added quote_role to the two stationary night blindness evidence items. Renamed the entry, this history directory and the OpenScientist report files from PDE6G-related_Retinopathy to PDE6G-Related_Retinopathy to match sibling entries; the report's artifact paths were updated to the new directory name, and this record's target slug and path point at the new file because the record had not yet merged.

OpenScientist ▸
Key Findings
openscientist-autonomous 10 citations 2026-10-30T23:45:22.997846

Key Findings

Finding 1 — PDE6G loss-of-function causes autosomal-recessive early-onset RP (RP57)

Dvir and colleagues performed genome-wide homozygosity mapping in two sibships of an extended consanguineous Muslim Arab-Israeli family with severe early-onset autosomal-recessive RP, mapping a shared 4.7-Mb homozygous region on chromosome 17q25.3 that contains PDE6G (PMID: 20655036). Sequencing of all coding exons and exon–intron boundaries revealed a homozygous single-base change, c.187+1G>T, in the conserved intron 3 donor splice site. The variant cosegregated with disease, and an in vitro splicing assay confirmed aberrant splicing. As the authors state: "Sequencing of all coding exons, including exon-intron boundaries, revealed a homozygous single base change (c.187+1G>T) located in the conserved intron 3 donor splice site of PDE6G." They further note that "One of the genes located in this interval is PDE6G, encoding for the inhibitory gamma subunit of rod photoreceptor cyclic GMP-phosphodiesterase." This established PDE6G as the causal gene of RP57 (MONDO:1040034). Evidence type: human clinical/genetic.

Finding 2 — Clinical phenotype: severe rod–cone dystrophy with extinguished ERG and macular edema

In the founding family, affected individuals had "markedly constricted visual fields" and "Both scotopic and photopic electroretinograms were severely reduced or completely extinct," indicating combined rod and cone dysfunction (PMID: 20655036). Funduscopy showed "typical bone spicule-type pigment deposits spread mainly at the midperiphery, as well as pallor of the optic disk." Macular involvement included loss of the foveal reflex and cystoid macular edema confirmed on optical coherence tomography (OCT). These features situate RP57 within the classic RP clinical spectrum (worldwide RP prevalence ~1/4000) but at the severe, early-onset end. Evidence type: human clinical.

Finding 3 — Mechanism: PDE6 γ-subunit loss dysregulates cGMP hydrolysis in rod outer segments, driving photoreceptor death

PDE6 is the central effector enzyme of the rod/cone phototransduction cascade — a tetramer of two catalytic subunits (rod PDE6A/PDE6B) and two inhibitory γ-subunits (rod PDE6G). As reviewed, "As the central effector enzyme of the G-protein coupled visual transduction pathway, activation of PDE6 catalysis causes a rapid decrease in cGMP levels that results in closure of cGMP-gated ion channels in the photoreceptor plasma membrane" (PMID: 34170501), and "mutations in PDE6 genes result in various retinal diseases that currently lack therapeutic treatment strategies." In vivo mouse studies of PDE6γ mutants demonstrate that the γ-subunit normally restrains dark PDE6 activity: ILE86TER rods "showed a decreased rate of decay of the photoresponse, consistent with decreased inhibition of PDE6 α and β by PDE6γ. Furthermore, ILE86TER rods had a higher rate of spontaneous activation of PDE6 than WT rods" (PMID: 21920434). Loss of Pγ therefore dysregulates cGMP signaling and reduces holoenzyme stability, the upstream lesion that triggers photoreceptor death. Evidence type: in vitro / model organism / review.

Finding 4 — Pde6g-deficient mouse recapitulates early-onset RP; PDE6-RP is gene-therapy-tractable even at late stages

A Pde6g preclinical mouse model exhibits "early onset and rapid rod degeneration, with the vast majority gone by P16," leading to retinal remodeling of inner retinal neurons, RPE, and vasculature, including acellular capillaries (PMID: 37363133) — faithfully reproducing the severe, early human phenotype. In the related Pde6b RP model, restoring the wild-type gene in rod photoreceptors produced "stable, sustained rescue of photoreceptor structure and function for at least 1 year, demonstrating gene therapy efficacy after onset of degeneration" (PMID: 29721933). A therapeutic window exists: "when fewer than 13% of rods remain, our genetic rescue halts photoreceptor degeneration, electroretinography (ERG) functional decline and inner retinal remodeling" at 16 weeks, whereas treatment at 24 weeks failed (PMID: 35195763). Evidence type: model organism.

Finding 5 — PDE6G-RP is an ultra-rare subtype within genetically heterogeneous RP (>90 genes)

RP is a group of inherited retinal diseases affecting >1 million people worldwide that "show tremendous genetic and phenotypic heterogeneity, involving over 90 genes in its causation" (PMID: 40575766); no curative treatment exists, though gene therapy, stem cells, optogenetics, retinal prosthetics, and pharmacotherapy are emerging. Within this landscape, PDE6G/RP57 is among the rarest causes — the defining disease was described in a single consanguineous Arab-Israeli kindred, against an overall RP prevalence of "1 in 4000" (PMID: 20655036). Evidence type: review / human clinical.

Finding 6 — Gene–drug interaction: PDE6-inhibiting drugs (sildenafil) selectively impair retinal function in PDE6-γ-deficient mice

In mice heterozygous for the Pde6g-null allele (PDEG tm1/+), the PDE5/PDE6 inhibitor sildenafil produced a reversible, dose-dependent decrease in ERG a- and b-wave amplitudes, while wild-type mice were unaffected: "ERGs of the PDEG:(tm1)/+ mice treated with sildenafil showed a reversible, dose-dependent decrease in a- and b-wave amplitudes. Wild-type mice treated with sildenafil did not show significant differences" (PMID: 11157892). This reveals heightened sensitivity of PDE6-γ-compromised retina to pharmacologic PDE6 inhibition and motivates a theoretical caution for carriers/patients exposed to PDE5/PDE6-cross-reactive drugs. Evidence type: model organism.

Finding 7 — gnomAD: PDE6G is LoF-tolerant in heterozygotes (recessive); carrier frequency ~1/6,600

gnomAD v4 shows PDE6G (ENSG00000185527; chr17:81,650,459–81,663,112; 4 exons) is not loss-of-function-constrained: pLI ≈ 0.0004, observed/expected LoF = 0.91 (observed 10 / expected 10.95), LoF Z = 0.24 — consistent with a recessive gene whose heterozygous LoF carriers are healthy. High-confidence truncating alleles are each ultra-rare (AF 1.4×10⁻⁶ to 6.8×10⁻⁶; e.g., p.Arg33Ter AC = 10, AF 6.8×10⁻⁶). The founding RP57 allele c.187+1G>T is present at AC = 2/1,461,730 (AF 1.37×10⁻⁶). Summing high-confidence LoF alleles gives q ≈ 7.6×10⁻⁵ → estimated carrier frequency ~1.5×10⁻⁴ (≈1 in 6,600) and random-mating affected frequency q² ≈ 5.8×10⁻⁹ (≈1 in 170 million). This quantitatively explains the ultra-rarity and consanguinity dependence; cases arise via homozygosity-by-descent, as in the founding family ("Genome-wide homozygosity mapping was conducted in two sibships from an extended consanguineous Muslim Arab Israeli family," PMID: 20655036). Evidence type: computational / population genomics.

Finding 8 — ClinVar documents a loss-of-function allelic series in PDE6G beyond the founding variant

ClinVar contains 149 PDE6G records (22 Pathogenic, 4 Likely pathogenic, 6 Conflicting, 66 VUS, 41 Likely benign, 8 Benign, 2 Benign/Likely benign). PDE6G-specific pathogenic/likely-pathogenic small variants include the founding splice-donor c.187+1G>T (Pathogenic), a second essential-splice variant c.146+1G>T (Pathogenic), the nonsense c.97C>T/p.Arg33Ter (Pathogenic), the frameshift c.69dup/p.Arg24fs (Pathogenic), and the start-loss c.2T>A/p.Met1Lys (Likely pathogenic); c.95del/p.Gln32fs and c.206del/p.Pro69fs are Conflicting. Large 17q25.3 copy-number gains (×3 duplications) and deletions spanning PDE6G are also catalogued as Pathogenic (contiguous multi-gene events). The founding c.187+1G>T allele anchors this series: "revealed a homozygous single base change (c.187+1G>T) located in the conserved intron 3 donor splice site of PDE6G" (PMID: 20655036). The uniform LoF nature of pathogenic alleles confirms a loss-of-function disease mechanism. Evidence type: variant database curation.

Finding 9 — Official HPO disease annotations for RP57 retrieved and integrated

The JAX HPO Annotation Network for OMIM:613582 (RP57; gene NCBIGene:5148 = PDE6G) returns ten phenotype annotations, all sourced to PMID: 20655036: Reduced visual acuity (HP:0007663, frequency 6/6), Constriction of peripheral visual field (HP:0001133, 4/4), Rod-cone dystrophy (HP:0000510), Spicular pigmentation of the retina (HP:0007737), Optic disc pallor (HP:0000543, young-adult onset), Absent foveal reflex (HP:0030825), Cystoid macular edema (HP:0011505), Attenuation of retinal blood vessels (HP:0007843), Childhood onset (HP:0011463), and Autosomal recessive inheritance (HP:0000007). The single source documents the constricted fields and extinguished rod+cone ERG that define the phenotype set. Evidence type: ontology curation / human clinical.

Section-by-Section Report

1. Disease Information

PDE6G-Related Retinopathy is Retinitis Pigmentosa 57 (RP57), a severe autosomal-recessive, early-onset rod–cone dystrophy caused by biallelic loss-of-function of PDE6G. It is an inherited retinal degeneration in which rod photoreceptors degenerate first, followed by cones, producing progressive loss of peripheral and night vision and eventual central visual loss.

Key identifiers:

Resource Identifier
OMIM (phenotype) #613582
OMIM (gene PDE6G) *180073 / 614494
MONDO MONDO:1040034 (also MONDO:0013315)
Gene (HGNC) HGNC:8788, PDE6G
NCBI Gene 5148
Ensembl ENSG00000185527
Locus 17q25.3

Synonyms: Retinitis pigmentosa 57; RP57; PDE6G-related retinitis pigmentosa. Information source type: Aggregated disease-level resources (OMIM, Orphanet, HPO, ClinVar, gnomAD) and primary literature, principally the founding family case series (not large EHR-derived cohorts).

2. Etiology

Causal factor: Purely genetic — biallelic loss-of-function variants in PDE6G. The founding pathogenic allele is the intron-3 essential-splice variant c.187+1G>T (PMID: 20655036); ClinVar documents additional nonsense, frameshift, essential-splice, and start-loss alleles plus 17q25.3 CNVs (Finding 8).

Genetic risk factors: The principal risk factor is consanguinity / homozygosity-by-descent. Because PDE6G is LoF-tolerant in heterozygotes (carrier ~1/6,600; Finding 7), affected individuals almost always inherit two null alleles identical by descent, so a family history of consanguinity dramatically raises risk. No common susceptibility loci or modifier genes are established.

Environmental risk factors: None established as causal. A pharmacologic gene–drug interaction exists (PDE6-cross-reactive inhibitors such as sildenafil selectively impair retinal function in PDE6-γ-deficient animals; Finding 6), which is a theoretical exacerbating exposure rather than a cause.

Protective factors: None specifically documented. By analogy to other RP forms, avoidance of excessive light exposure and general ocular health measures are prudent but unproven for RP57.

Gene–environment interactions: The best-documented interaction is pharmacologic (PDE6-inhibitor sensitivity; Finding 6). No dietary or toxicant GxE interactions are established.

3. Phenotypes

All ten official HPO annotations derive from the founding family (PMID: 20655036); see Finding 9.

Phenotype HPO term Type Frequency Onset/Course
Rod-cone dystrophy HP:0000510 Clinical sign (ERG/functional) Characteristic Childhood onset, progressive
Reduced visual acuity HP:0007663 Symptom 6/6 Progressive
Constriction of peripheral visual field HP:0001133 Clinical sign 4/4 Progressive
Spicular (bone-spicule) retinal pigmentation HP:0007737 Physical manifestation Characteristic Midperipheral
Optic disc pallor HP:0000543 Clinical sign Present Young-adult onset (HP:0011462)
Absent foveal reflex HP:0030825 Clinical sign Present —
Cystoid macular edema HP:0011505 Clinical sign (OCT) Present Variable
Attenuation of retinal blood vessels HP:0007843 Clinical sign Present Young-adult onset
Childhood onset HP:0011463 Onset modifier — —
Autosomal recessive inheritance HP:0000007 Inheritance modifier — —

Severity: Severe — scotopic and photopic ERGs are severely reduced or extinguished, indicating combined rod and cone dysfunction. Progression: Progressive, consistent with RP natural history. Quality-of-life impact: Severe and lifelong — progressive peripheral then central vision loss causes major functional disability (mobility, reading, driving), with cystoid macular edema further threatening central acuity. Disease-specific QoL instruments for RP57 are not available; general RP QoL burden applies.

4. Genetic / Molecular Information

Causal gene: PDE6G (HGNC:8788; Gene 5148; ENSG00000185527; 17q25.3; 4 exons) encoding Pγ, the 87-aa inhibitory γ-subunit of rod PDE6.

Pathogenic variants (ClinVar; Finding 8):

Variant Protein Type Classification
c.187+1G>T — (intron-3 donor) Essential splice Pathogenic (founding allele)
c.146+1G>T — Essential splice Pathogenic
c.97C>T p.Arg33Ter Nonsense Pathogenic
c.69dup p.Arg24fs Frameshift Pathogenic
c.2T>A p.Met1Lys Start-loss Likely pathogenic
c.95del p.Gln32fs Frameshift Conflicting
c.206del p.Pro69fs Frameshift Conflicting
17q25.3 gains/deletions — CNV (multi-gene) Pathogenic

Variant class: All established pathogenic small variants are loss-of-function (nonsense, frameshift, essential-splice, start-loss). Allele frequencies (gnomAD v4; Finding 7): all ultra-rare — c.187+1G>T AF 1.37×10⁻⁶; p.Arg33Ter AF 6.8×10⁻⁶; summed high-confidence LoF q ≈ 7.6×10⁻⁵. Origin: Germline. Functional consequence: Loss of function (loss of the inhibitory γ-subunit; reduced holoenzyme stability and dysregulated dark PDE6 activity — Finding 3).

Modifier genes: None established for RP57. Epigenetic information: None specifically reported for this disease. Chromosomal abnormalities: Large 17q25.3 copy-number gains and deletions spanning PDE6G are catalogued in ClinVar as contiguous multi-gene events rather than isolated PDE6G lesions.

5. Environmental Information

Environmental factors: None causal. Lifestyle factors: None established. Infectious agents: Not applicable — RP57 is a monogenic inherited retinal degeneration. The one relevant non-genetic consideration is iatrogenic: systemic PDE6-cross-reactive inhibitors (sildenafil and related PDE5 inhibitors) selectively reduce retinal function in PDE6-γ-deficient animals (Finding 6), suggesting a theoretical avoidance recommendation.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. A biallelic loss-of-function variant in PDE6G (e.g., c.187+1G>T essential-splice) leads to absent or non-functional rod Pγ inhibitory subunit. (Demonstrated: founding family + splicing assay, [PMID: 20655036].)
  2. Loss of Pγ results in loss of inhibitory control over the rod PDE6 catalytic dimer (PDE6A/PDE6B) and reduced PDE6 holoenzyme expression/stability. (Demonstrated in vivo in PDE6γ-mutant mice: increased spontaneous dark PDE6 activity, [PMID: 21920434].)
  3. Dysregulated PDE6 catalysis leads to abnormal cGMP hydrolysis and disrupted cGMP homeostasis in rod outer segments (the cascade in which PDE6 activation normally drops cGMP to close CNG channels, [PMID: 34170501]). (Inferred for the human null state from the central role of PDE6 in phototransduction.)
  4. Disrupted cGMP/CNG-channel signaling and phototransduction failure result in rod photoreceptor dysfunction (extinguished scotopic ERG) and lead to rapid rod photoreceptor death. (Demonstrated in the Pde6g mouse: most rods gone by P16, [PMID: 37363133].)
  5. Rod loss leads to secondary (non-cell-autonomous) cone photoreceptor death — the branch producing extinguished photopic ERG and eventual central vision loss. (Inferred from the extinguished photopic ERG in patients [PMID: 20655036] and the general RP paradigm of secondary cone death.)
  6. Progressive photoreceptor loss results in inner-retinal remodeling, RPE and vascular changes (attenuated vessels, acellular capillaries), bone-spicule pigment migration, optic disc pallor, and cystoid macular edema — the clinical RP phenotype. (Demonstrated remodeling in the Pde6g mouse, [PMID: 37363133]; clinical signs, [PMID: 20655036].)

Molecular pathway: Rod cGMP phototransduction (G-protein-coupled; rhodopsin → transducin → PDE6 → cGMP/CNG channel). Cellular processes: Photoreceptor cell death (apoptosis/remodeling), retinal remodeling. Protein dysfunction: Loss of function of Pγ, the intrinsically disordered inhibitory subunit, with loss of holoenzyme regulation and stability. Biochemical abnormality: Dysregulated cGMP-specific phosphodiesterase activity → cGMP imbalance. Metabolic link: cGMP second-messenger metabolism.

Suggested GO terms: phototransduction (GO:0007602); detection of light stimulus involved in visual perception (GO:0050908); cGMP metabolic process (GO:0046068); 3',5'-cyclic-GMP phosphodiesterase activity (GO:0047555); photoreceptor cell maintenance (GO:0045494); regulation of rhodopsin mediated signaling pathway (GO:0022400). Suggested CL terms: retinal rod cell (CL:0000604), retinal cone cell (CL:0000573), retinal pigment epithelial cell (CL:0002586). Suggested CHEBI: cGMP (CHEBI:16356).

7. Anatomical Structures Affected

  • Organ: Eye (UBERON:0000970); retina (UBERON:0000966). Body system: Visual/nervous (sensory). Secondary: optic nerve/disc (pallor), retinal vasculature (attenuation), macula (cystoid edema).
  • Tissue/cell: Neural retina; primary target rod photoreceptors (CL:0000604), secondary cone photoreceptors (CL:0000573); downstream RPE (CL:0002586) and inner retinal neurons (remodeling).
  • Subcellular: Rod outer segment (GO:0001750, photoreceptor outer segment), where PDE6 operates; photoreceptor connecting cilium/disc membranes.
  • Localization: Bilateral, roughly symmetric; pigmentary changes predominate in the midperiphery with later macular involvement (macula lutea UBERON:0001782 / fovea UBERON:0000401).

8. Temporal Development

Onset: Childhood (HP:0011463), early-onset severe disease. Onset pattern: Insidious/chronic-progressive. Progression: Progressive rod-then-cone degeneration; rapid in the mouse model (most rods lost by P16, [PMID: 37363133]), with early severe/extinguished ERG in humans. Course: Chronic, lifelong, progressive; no spontaneous remission. Critical period / therapeutic window: Model data define a window in which gene supplementation can halt degeneration while sufficient photoreceptors remain (rescue effective with <13% rods remaining at 16 weeks but not at 24 weeks in the Pde6b model; [PMID: 35195763]) — implying earlier intervention is essential.

9. Inheritance and Population

Inheritance: Autosomal recessive (HP:0000007). Penetrance: Presumed complete in biallelic LoF homozygotes/compound heterozygotes (consistent across the founding family). Expressivity: Severe; limited data preclude firm expressivity statements. Anticipation: Not applicable (not a repeat-expansion disorder). Carrier frequency: ~1 in 6,600 (gnomAD-derived; Finding 7). Affected frequency (random mating): ~1 in 170 million (q²), so observed cases cluster in consanguineous families. Founder effect: The c.187+1G>T allele was described in a single extended consanguineous Muslim Arab-Israeli kindred ([PMID: 20655036]); no broad founder population is established. Consanguinity: Central to disease occurrence. Epidemiology: Ultra-rare; no prevalence/incidence estimates exist specifically for RP57; it is one of the rarest contributors to RP (overall RP ~1/4000; >90 genes). Sex ratio: Expected ~1:1 (autosomal). Geographic distribution: No endemic distribution established beyond the index family.

10. Diagnostics

Clinical/functional tests: Full-field electroretinography (ERG) is the key functional test — scotopic and photopic responses are severely reduced or extinguished. OCT documents macular structure and cystoid macular edema. Fundus examination / autofluorescence shows bone-spicule pigmentation, vascular attenuation, optic disc pallor. Visual field testing (perimetry) quantifies peripheral constriction. Biomarkers: No specific biochemical/circulating biomarker; the diagnosis is genetic. Genetic testing (definitive): Because RP is genetically heterogeneous (>90 genes), next-generation sequencing gene panels for inherited retinal dystrophies or whole-exome/whole-genome sequencing are the recommended first-line approach; PDE6G is included on comprehensive IRD panels. Homozygosity mapping is valuable in consanguineous pedigrees (the discovery method; [PMID: 20655036]). Chromosomal microarray can detect the 17q25.3 CNVs catalogued in ClinVar. Differential diagnosis: Other PDE6-related RP (PDE6A, PDE6B), congenital stationary night blindness (PDE6B H258N), other autosomal-recessive RP genes, syndromic RP (Usher, Bardet-Biedl) — distinguished by extra-ocular features and molecular testing. Screening: Cascade carrier testing in affected families and carrier screening in consanguineous couples; no population newborn screening exists.

11. Outcome / Prognosis

Survival/mortality: RP57 is non-lethal; it does not reduce life expectancy. Morbidity: Significant, progressive visual disability — the dominant outcome is severe, eventually profound, bilateral vision loss with functional blindness in advanced stages. Disease course: Progressive and lifelong; complications include cystoid macular edema (threatens central acuity) and the mobility/independence impacts of field loss. Recovery: No spontaneous recovery; vision loss is irreversible without intervention. Prognostic factors: Residual photoreceptor count and age at any future therapeutic intervention are the key determinants (therapeutic-window data from PDE6 models; [PMID: 35195763]). Prognostic biomarkers: None validated beyond structural (OCT ellipsoid zone/outer nuclear layer) and functional (ERG) measures used generally in RP.

12. Treatment

Current standard: No approved disease-modifying therapy. Management is supportive: low-vision rehabilitation and visual aids, orientation and mobility training, treatment of cystoid macular edema (e.g., carbonic anhydrase inhibitors, used generally in RP-CME), and genetic counseling. Vitamin A supplementation is debated in RP generally and not specifically validated for RP57.

Experimental / leading candidate — gene therapy: AAV-mediated gene supplementation is the most promising approach. In the related Pde6b model, wild-type gene restoration produced durable (≥1 year) rescue even after degeneration onset ([PMID: 29721933]), with a defined window of efficacy ([PMID: 35195763]); the Pde6g mouse provides a model to test PDE6G supplementation ([PMID: 37363133]). Emerging modalities broadly under investigation for RP include gene therapy, stem cells, optogenetics, retinal prosthetics, and pharmacotherapy ([PMID: 40575766]).

Pharmacogenomic caution: PDE5/PDE6-cross-reactive inhibitors (e.g., sildenafil) selectively impair retinal function in PDE6-γ-deficient animals ([PMID: 11157892]) and should be used cautiously in PDE6G patients/carriers.

Suggested NCIT terms: Gene Therapy (NCIT:C15431); Supportive Care (NCIT:C15277); Rehabilitation Therapy (NCIT:C15917).

13. Prevention

  • Primary prevention: Not applicable (genetic). The principal lever is genetic counseling for consanguineous families and at-risk carriers.
  • Genetic screening: Cascade carrier testing in families with a proband; carrier screening for consanguineous couples; preimplantation genetic testing (PGT) and prenatal diagnosis are options once the familial variant is known.
  • Secondary prevention: Early molecular diagnosis to enable timely intervention within the therapeutic window and early management of cystoid macular edema.
  • Tertiary prevention: Low-vision rehabilitation and complication management.
  • Pharmacologic avoidance: Caution with PDE6-cross-reactive inhibitors (Finding 6).

14. Other Species / Natural Disease

Taxonomy / orthologs: PDE6G is conserved across vertebrates; mouse ortholog Pde6g (NCBI Gene 18587). Model-organism disease: Engineered Pde6g-deficient mice recapitulate early-onset rapid rod degeneration ([PMID: 37363133]). Natural animal disease: Naturally occurring PDE6-related retinal degenerations are well documented in dogs for the catalytic subunits — e.g., PDE6B-null rcd1 and PDE6A-related forms — which model the human catalytic-subunit RP forms; a naturally occurring canine PDE6G retinopathy is not specifically established in the reviewed literature. Comparative biology: The rod phototransduction cascade and PDE6 holoenzyme architecture are evolutionarily conserved, so mechanisms translate across mammals. Of note, cross-species isoform differences exist (e.g., rod PDE6G can functionally substitute in cones in mouse; [PMID: 25739440]), a caveat for extrapolation. Zoonotic potential: None (non-infectious, genetic).

15. Model Organisms

Model Type Key features Reference
Pde6g-deficient mouse (preclinical RP model) Mammalian, genetic null Early-onset, rapid rod degeneration (most rods gone by P16); inner-retinal, RPE, and vascular remodeling incl. acellular capillaries PMID: 37363133
PDE6γ ILE86TER transgenic (on Pde6g-null background) Mammalian, knock-in/transgenic Decreased photoresponse decay, increased spontaneous dark PDE6 activity, reduced PDE6 expression — defines Pγ inhibitory/stabilizing role PMID: 21920434
PDEG tm1/+ (Pde6g-null heterozygote) Mammalian Sildenafil-induced reversible ERG suppression (gene–drug interaction) PMID: 11157892
Pde6b RP mouse (related subunit) Mammalian Gene-supplementation rescue durable ≥1 yr; defined therapeutic window PMID: 29721933, PMID: 35195763

Phenotype recapitulation: The Pde6g mouse strongly recapitulates the human severe, early-onset rod–cone degeneration. Limitations: Mouse retinas are rod-dominant and lack a macula/fovea, so cystoid macular edema and foveal phenotypes are not modeled; cross-species PDE6 isoform substitution ([PMID: 25739440]) can also modify phenotype. Applications: Mechanistic dissection of Pγ loss and preclinical testing of AAV gene supplementation and therapeutic-window timing. Resources: MGI, IMPC/IMSR for Pde6g alleles.

Mechanistic Model / Interpretation

  PDE6G biallelic LoF variant (e.g., c.187+1G>T essential splice)   [Finding 1, 8]
         │  leads to
         ▼
     Absent / non-functional rod Pγ inhibitory subunit
         │  results in
         ▼
  Loss of inhibitory control of PDE6 catalytic dimer (A/B)
  + reduced PDE6 holoenzyme stability/expression                    [Finding 3]
         │  leads to
         ▼
   Dysregulated cGMP hydrolysis in rod outer segments
   (abnormal cGMP / CNG-channel gating; phototransduction failure)  [Finding 3]
         │  results in
         ▼
Rod dysfunction (extinguished scotopic ERG)
         │  leads to
         ▼
Rapid ROD photoreceptor death                               [Finding 2, 4]
    │              │
       leads to     │              │ leads to (secondary, non-cell-autonomous)
    ▼              ▼
   Inner-retinal / RPE /      CONE photoreceptor death
   vascular REMODELING        (extinguished photopic ERG)
   (bone spicules, vessel          │
    attenuation, disc pallor,      │ leads to
    cystoid macular edema)         ▼
    └──────►  Progressive peripheral → central
              VISION LOSS (clinical RP57)           [Finding 2, 9]

The disease is mechanistically clean: a single recessive loss-of-function lesion in a non-redundant, rod-specific regulatory subunit removes the brake on the central phototransduction effector enzyme, dysregulating the second messenger (cGMP) that photoreceptors depend on for survival. This places RP57 firmly among the PDE6-related retinopathies (alongside PDE6A, PDE6B, PDE6C/PDE6H forms), differing by which subunit is lost but converging on cGMP dysregulation and photoreceptor death. Because the defect is loss-of-function (not a toxic gain-of-function), gene supplementation is mechanistically rational — simply restoring Pγ should reconstitute holoenzyme regulation — and related-subunit models confirm durable rescue within a therapeutic window.

Evidence Base

PMID Role How it supports/challenges findings
20655036 Founding/defining Establishes PDE6G causality (c.187+1G>T), clinical phenotype, inheritance; sole source for all 10 HPO annotations. Supports F001, F002, F005, F007, F008, F009.
34170501 Mechanism (review) PDE6 as central phototransduction effector; links PDE6-gene mutations to untreated retinal disease. Supports F003.
21920434 Mechanism (in vivo) PDE6γ restrains dark PDE6 activity; loss dysregulates cGMP signaling and reduces expression. Supports F003.
37363133 Model organism Pde6g mouse recapitulates early-onset rapid rod loss + remodeling. Supports F004.
29721933 Therapeutic (model) Durable gene-supplementation rescue after onset in PDE6 RP. Supports F004.
35195763 Therapeutic (model) Defines therapeutic window (<13% rods rescuable at 16 wk, fails at 24 wk). Supports F004.
40575766 Context (review) RP heterogeneity (>90 genes), emerging therapies. Supports F005.
11157892 Gene–drug interaction Sildenafil selectively suppresses ERG in Pde6g-null heterozygotes. Supports F006.
33860373, 32898583, 39739818 Structural/mechanistic PDE6 structure, Pγ regulation, allosteric activation — background for gene-supplementation and allosteric-activator strategies.

Limitations and Knowledge Gaps

  1. Single defining pedigree. The disease phenotype rests almost entirely on one consanguineous family ([PMID: 20655036]); all 10 HPO annotations come from this single source, limiting confidence in frequency estimates, expressivity, and the full phenotypic range.
  2. No human natural-history or epidemiologic data specific to RP57 (no prevalence/incidence, no longitudinal visual-decline rates, no QoL instruments).
  3. Human mechanistic data are extrapolated from PDE6 biology and mouse/in-vitro models; the precise cGMP dynamics and cell-death pathway in human PDE6G-null retina are inferred, not directly measured.
  4. No PDE6G-specific therapeutic data. Gene-therapy evidence derives from the related Pde6b model; a PDE6G gene-supplementation proof-of-concept in the Pde6g mouse is a gap.
  5. Carrier/affected frequency estimates are computational (gnomAD-derived), subject to ascertainment and reference-population limits.
  6. Cross-species isoform caveats (e.g., rod PDE6G substituting in mouse cones; [PMID: 25739440]) complicate translation of mouse phenotypes to human cone involvement.

Proposed Follow-up Experiments / Actions

  1. Expand the genotype–phenotype series. Aggregate additional PDE6G biallelic cases via IRD registries and matchmaking (GeneMatcher) to validate the HPO frequency set, establish expressivity, and detect modifiers.
  2. PDE6G-specific gene supplementation. Test AAV-PDE6G (rod-targeted) in the Pde6g mouse to confirm rescue and map the human-relevant therapeutic window, mirroring the Pde6b paradigm ([PMID: 29721933], [PMID: 35195763]).
  3. Natural-history study. Longitudinal OCT (ellipsoid zone/ONL), ERG, and perimetry in any identifiable patients to define progression rate and optimal intervention timing.
  4. cGMP-pathway pharmacology. Evaluate PDE6 allosteric modulators and cGMP-lowering/CNG-modulating strategies ([PMID: 32898583], [PMID: 34170501]) as non-genetic adjuncts, and formally document the sildenafil/PDE6-inhibitor caution in clinical guidance.
  5. Variant curation. Reclassify the Conflicting frameshift alleles (c.95del, c.206del) with functional splicing/expression assays to firm up the LoF allelic series.
  6. iPSC retinal organoids from patient cells to model human PDE6G-null photoreceptor degeneration and test editing/supplementation in a human context.

Evidence-source legend: human clinical/genetic (founding family, registries), model organism (mouse Pde6g/Pde6b), in vitro/structural (PDE6 biochemistry/cryo-EM), computational (gnomAD, ClinVar curation).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome Count
References checked 12
Resolved 12
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 12
On topic 10
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 35
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 4
Terms whose name was checked 14
Terms named correctly 10
Terms named as a different term 0
Terms whose name is worth a second look 4

Terms whose name is worth a second look

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

  • HP:0007737 (2 mentions) - the report calls it "Spicular (bone-spicule) retinal pigmentation"; HP calls it Spicular pigmentation of the retina, and lists "Bone corpuscle fundus pigmentation" among its other names
  • CL:0000604 (2 mentions) - the report calls it "rod photoreceptors"; CL calls it retinal rod cell, and lists "rod" among its other names
  • CL:0000573 (2 mentions) - the report calls it "cone photoreceptors"; CL calls it retinal cone cell, and lists "cone" among its other names
  • UBERON:0000970 (1 mention) - the report calls it "Organ: Eye"; UBERON calls it eye**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Gene, OMIM, NCBIGene.

31 of 35 terms resolved to a current term; the rest could not be looked up either way.