CNGA1-Related Retinopathy

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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0013405 retinitis pigmentosa 49 Not Yet Curated

MONDO places retinitis pigmentosa 49 (OMIM:613756, retinitis pigmentosa caused by mutation in CNGA1) as the single child of MONDO:0800405. All reported CNGA1 disease presents as autosomal recessive retinitis pigmentosa, so the subtype is captured as a mapping rather than a separate has_subtypes row.

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Inheritance

1

Autosomal recessive HP:0000007

CNGA1-related retinopathy is caused by biallelic (homozygous or compound heterozygous) pathogenic CNGA1 variants. Heterozygous carriers are unaffected.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:7479749 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Five mutant sequences cosegregated with disease among four unrelated families with autosomal recessive RP."

The gene-discovery study found CNGA1 variants cosegregating with disease in autosomal recessive families.

PMID:15570217 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The mutation is found in a homozygous state in all 7 affected individuals and was heterozygous in all 15 unaffected family members examined."

Linkage and segregation in a consanguineous family show that homozygotes are affected and heterozygous carriers are not.

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Discussions and Knowledge Gaps

2

Which intermediates link CNGA1 channel loss and cGMP accumulation to rod death?

KNOWLEDGE GAP OPEN cnga1_cgmp_death_intermediates

Attached to

pathophysiology#Rod cGMP Accumulation pathophysiology#Progressive Rod Photoreceptor Degeneration

In CNGA1-deficient mice, cGMP accumulates, microglia activate, oxidative damage appears and chaperone-mediated autophagy coincides with rod death, and gene augmentation reverses cGMP accumulation while preserving rods. None of these studies isolates which event is causal for death. A null channel removes the cGMP-gated calcium influx, so the route from cGMP accumulation to death may differ from degenerations in which the open channel overloads the rod with calcium.

Show evidence (1 reference)

PMID:34418172 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In addition, the down-regulated PI3K-AKT-mTOR pathway indicated upregulation of autophagic process, and chaperone-mediated autophagy was further shown to coincide with the time course of photoreceptor death."

Temporal coincidence, not causation, between autophagy and photoreceptor death.

Why do Cnga1-deficient mice lose photoreceptors within months while patients keep central acuity for decades, and which model predicts response to treatment at a human-relevant stage?

HUMAN MODEL MISMATCH OPEN cnga1_mouse_progression_mismatch

Attached to

animal_models#Cnga1 knockout mouse (CRISPR/Cas9) treatments#AAV-Mediated CNGA1 Gene Augmentation Therapy

The CRISPR knockout loses most photoreceptors by 6 months and was treated at postnatal day 14, before major rod loss, whereas the Y509C mouse degenerates more slowly for unknown reasons. Patients present after years of rod loss but with preserved foveal photoreceptors. Rescue after treatment at a later stage has not been tested in a CNGA1 model.

Show evidence (1 reference)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In the current study, we treated Cnga1-/- mice at an early stage of the disease to assess the maximal potential of gene augmentation therapy; however, patients with RP are often diagnosed at a later stage of the disease."

The authors identify the treatment-stage gap themselves.

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Pathophysiology

6

Biallelic CNGA1 Loss of Function

Mechanism confidence: Established

Biallelic pathogenic CNGA1 variants remove or disable the alpha subunit of the rod cGMP-gated channel. Early nonsense and frameshift alleles and whole-gene deletion are expected to encode no functional channel; missense and distal frameshift alleles that have been expressed in vitro reduce membrane targeting, abundance or channel function. Not every reported missense variant is pathogenic, and functional testing has reclassified many variants of uncertain significance.

CNGA1 hgnc:2148 ↓ DECREASED

Genetic context CNGA1 hgnc:2148 variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic germline CNGA1 variants, homozygous or compound heterozygous; most are truncating, with a smaller set of missense alleles shown to impair channel expression or function.

cGMP-gated cation channel activity GO:0005223 ↓ DECREASED

Downstream

Defective Rod CNG Channel Membrane Expression Loss or misfolding of CNGA1 prevents assembly or surface delivery of the heteromeric rod channel.

Show evidence (3 references)

PMID:7479749 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two of these were nonsense mutations early in the reading frame (Glu76End and Lys139End) and one was a deletion encompassing most if not all of the transcriptional unit; these three alleles would not be expected to encode a functional channel."

The original patient alleles include early nonsense variants and a whole-gene deletion predicted to abolish the channel.

PMID:25268133 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Consequently, three CNGA1 frameshift mutations (c.191delG, c.265delC and c.1429delG) were identified as arRP-causing mutations in five patients"

All causal alleles in the Japanese cohort were frameshifts removing functional domains of the channel.

PMID:42192302 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The aequorin-based assay showed that 72.1% of tested variants significantly impaired CNG channel function and were classified as functionally abnormal, while 23.3% were functionally normal and 5% remained functionally uncertain."

A functional screen of disease-associated missense variants shows that most impair channel function while a minority behave normally, so missense alleles need functional or segregation support.

Defective Rod CNG Channel Membrane Expression

Mechanism confidence: Established

The native rod channel is a 3:1 CNGA1:CNGB1 heterotetramer in the outer-segment plasma membrane. Mutant CNGA1 proteins expressed in vitro are retained inside the cell or reach the membrane at reduced levels, and one C-terminal frameshift abolishes surface expression only when coexpressed with CNGB1. In a Cnga1 point-mutant mouse, CNGA1 protein is lost and the CNGB1 partner protein is also undetectable despite normal transcript levels, so the outer segment lacks the channel complex.

retinal rod cell CL:0000604

cGMP-gated cation channel activity GO:0005223 ↓ DECREASED

photoreceptor outer segment GO:0001750

Animal models

Cnga1 Y509C mouse (ENU-derived) Mouse recapitulates Both channel subunits are lost from rod outer segments despite normal transcript levels.

Downstream

Loss of Rod Light Responses Without outer-segment cGMP-gated channels, light-driven closure of the dark current cannot generate a rod response.

Show evidence (6 references)

PMID:7479749 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The latter two mutations were expressed in vitro and found to encode proteins that were predominantly retained inside the cell instead of being targeted to the plasma membrane."

Heterologous expression of the Ser316Phe and Arg654 frameshift alleles shows failure of plasma membrane targeting.

PMID:11970862 SUPPORT DIRECT PRIMARY RESULT In Vitro

"As native retinal rod CNG channels comprise CNGA1 and CNGB1 subunits, we coexpressed CNGA1-RP and CNGB1. Surprisingly, this subunit combination did not produce detectable channels at the membrane surface."

In Xenopus oocytes the disease-associated CNGA1 truncation forms normal homomers but prevents surface expression of the native-type heteromer with CNGB1.

PMID:26802146 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The mut CNGA1 p.(G513R) protein was largely retained inside the cell rather than being targeted to the plasma membrane"

A patient missense allele in the cyclic nucleotide-binding domain is retained intracellularly in vitro.

+ 3 more references

Loss of Rod Light Responses

Mechanism confidence: Established

Rods lacking CNGA1 channels do not generate light responses. In Cnga1 knockout and Cnga1 Y509C mice, rod-driven ERG responses are absent from the earliest recordings, before extensive photoreceptor loss. In patients, scotopic ERG responses are severely reduced or nonrecordable.

retinal rod cell CL:0000604

phototransduction GO:0007602 ↓ DECREASED

Animal models

Cnga1 knockout mouse (CRISPR/Cas9) Mouse recapitulates Rod-specific ERG responses are absent from one month.

Cnga1 knockout mouse (CRISPR/Cas9) Mouse rescues Subretinal AAV8-hRHO-mCnga1 at postnatal day 14 restores correctly localized CNGA1, rod-mediated ERG and vision-guided behaviour for at least 8.5 months.

Downstream

Rod cGMP Accumulation Channel-deficient rods accumulate cGMP; gene augmentation reverses this in treated retina.

Progressive Rod Photoreceptor Degeneration Loss of rod function precedes progressive rod death in CNGA1-deficient mice; the intermediates connecting channel loss to death are not fully resolved.

Nyctalopia Loss of rod-mediated vision impairs vision in dim light.

Undetectable electroretinogram Loss of the rod light response removes the rod-driven ERG; later cone loss extinguishes the remaining photopic response.

Show evidence (3 references)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"These observations suggest that the rod system is not functional in the Cnga1-/- mouse."

Scotopic ERGs in the knockout lack a rod-specific response and rod-derived a-wave components.

PMID:36115851 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Consistent with the loss of rod CNG channel function, we observed an absence of rod-driven ERG responses (a- and b-wave) from the earliest observation time point (PW3)."

An independent point-mutant model shows absent rod-driven responses from postnatal week 3.

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Scotopic responses in these patients were severely reduced or nonrecordable, whereas photopic responses were relatively preserved, although attenuated."

In the minority of patients with recordable ERGs, the rod system is disproportionately affected.

Rod cGMP Accumulation

Mechanism confidence: Provisional

Untreated Cnga1-/- retina shows abnormally high cGMP immunoreactivity, and AAV-mediated CNGA1 expression reverses it in treated regions. The study describes the accumulation as a feature of impaired CNG channel function that triggers photoreceptor death, citing other work; the death-effector pathway was not measured in CNGA1 models.

retinal rod cell CL:0000604

Animal models

Cnga1 knockout mouse (CRISPR/Cas9) Mouse rescues Treated retina loses the abnormal cGMP immunoreactivity seen in untreated eyes.

Downstream

Progressive Rod Photoreceptor Degeneration Abnormal cGMP accumulation is proposed to contribute to rod death; the causal step has not been isolated in CNGA1 models.

Show evidence (1 reference)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We found that this toxic accumulation was reversed in the treated retina, whereas cGMP levels remained high in untreated eyes"

Immunohistochemistry shows high cGMP in untreated Cnga1-/- retina and its reversal after CNGA1 gene augmentation.

Progressive Rod Photoreceptor Degeneration

Mechanism confidence: Established

Rods degenerate after loss of function. In the CRISPR Cnga1 knockout the outer nuclear layer thins almost linearly and is nearly gone by 6 months, with TUNEL-positive photoreceptors, microglial activation and oxidative damage, and transcriptomic evidence of reduced PI3K-AKT-mTOR signalling with chaperone-mediated autophagy coinciding with photoreceptor death. The Y509C point mutant degenerates more slowly. In patients, ellipsoid-zone width declines over years and fundus changes of retinitis pigmentosa accumulate.

retinal rod cell CL:0000604 microglial cell CL:0000129

microglial cell activation GO:0001774 ↑ INCREASED chaperone-mediated autophagy GO:0061684 ↑ INCREASED

Animal models

Cnga1 knockout mouse (CRISPR/Cas9) Mouse partially recapitulates Progressive TUNEL-positive photoreceptor loss with microglial activation and oxidative damage.

Downstream

Secondary Cone Degeneration Cone function and structure decline after rod loss; the non-cell-autonomous intermediates are unresolved.

Constriction of peripheral visual field Progressive loss of peripheral photoreceptors narrows the visual field.

Spicular pigmentation of the retina Pigment migrates into the degenerating retina and clumps in a bone-spicule pattern as photoreceptors are lost.

Attenuation of retinal blood vessels Retinal vessel attenuation is a secondary change of long-standing retinal degeneration.

Optic disc pallor Waxy disc pallor reflects long-standing retinal degeneration.

Show evidence (5 references)

PMID:34418172 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Immunofluorescence and TUNEL staining showed progressive degeneration in rods and cones. Moreover, microglial activation and oxidative stress damage occurred in parallel."

The knockout shows progressive TUNEL-positive photoreceptor degeneration with concurrent microglial activation and oxidative damage; the order of these events is not resolved.

PMID:34418172 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"In addition, the down-regulated PI3K-AKT-mTOR pathway indicated upregulation of autophagic process, and chaperone-mediated autophagy was further shown to coincide with the time course of photoreceptor death."

Chaperone-mediated autophagy coincides with photoreceptor death; whether it drives or responds to degeneration is not established.

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The thickness of ONL reduced to 46% of the wild-type at the age of 3 months and became hardly discernible by the age of 6 months"

OCT quantifies progressive photoreceptor nuclear layer loss in the knockout.

+ 2 more references

Secondary Cone Degeneration

Mechanism confidence: Established

Cones degenerate after rod loss. In the knockout, cone-mediated ERG responses pass through a transient supernormal phase and then decline with cone morphology compromised; in the Y509C mouse, cone outer segments are lost by 9 months and cones by 12 months. In patients, central acuity is usually preserved for decades before declining, and advanced disease involves the whole retina.

retinal cone cell CL:0000573

Animal models

Cnga1 Y509C mouse (ENU-derived) Mouse recapitulates Cone-mediated responses decline secondarily and cones are lost by 12 months.

Downstream

Rod-cone dystrophy Rod-first, cone-second degeneration produces the rod-cone dystrophy pattern.

Reduced visual acuity Loss of central cone function reduces visual acuity, usually after the third decade; cataract and macular complications also contribute.

Macular atrophy Advanced disease extends to the macula with atrophic and pigmentary changes.

Undetectable electroretinogram Loss of cones removes the residual photopic response, leaving a nonrecordable ERG in most adult patients.

Show evidence (3 references)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In summary, the ERG analysis indicates a lack of rod-driven response in the Cnga1-/- mouse, and reveals a progressive loss of cone-mediated function with an initial 'supernormal' phase."

Cone function in the knockout declines progressively after an early supernormal period.

PMID:36115851 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Over time, a gradual reduction of PNA signal was observed, revealing a loss of the outer segments of cones at PM9 and a complete loss of the cones at PM12"

Histology shows delayed but complete cone loss in the point-mutant model.

PMID:25268133 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Retinal degeneration in the macular region and severely decreased BCVA occurred in 3/5 patients suggesting that the advanced stage of CNGA1 mutations included degeneration of the entire retina with both rod and cone photoreceptors."

Macular degeneration and reduced acuity in advanced patients indicate cone involvement; the inference to cone loss is the authors' interpretation of clinical findings.

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Pathograph

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Phenotypes

14

Cardiovascular 1

Attenuation of retinal blood vessels VERY_FREQUENT HP:0007843

Show evidence (2 references)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Fundus photography (40 patients available) revealed generalized vascular attenuation in all eyes."

Vascular attenuation was universal among photographed patients.

PMID:25268133 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Funduscopy showed retinal degeneration with pigmentation and attenuation of retinal vessels in all patients"

Present in all five Japanese patients.

Eye 13

Nyctalopia VERY_FREQUENT HP:0000662

Show evidence (3 references)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Nyctalopia was the initial symptom in all patients (100%), with a mean age at onset of 4.4 ± 2.7 years."

Night blindness was universal and of early-childhood onset in 57 East Asian patients.

PMID:41448483 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Night blindness was the universal initial symptom, with most patients (88%) experiencing onset during childhood."

A separate 58-patient Chinese cohort confirms night blindness as the universal presenting symptom.

PMID:25268133 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All five patients reported that they noticed night blindness from childhood."

Childhood night blindness in every Japanese patient with biallelic CNGA1 variants.

Rod-cone dystrophy VERY_FREQUENT HP:0000510

Show evidence (1 reference)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Consistent with a diagnosis of RP, all patients exhibited rod-cone dysfunction with high interocular symmetry"

All 39 patients with full-field ERG had rod-cone dysfunction.

Undetectable electroretinogram FREQUENT HP:0000550

Show evidence (2 references)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Residual responses were detected in only 9 of 39 patients (23%), and these patients were significantly younger than those with nonrecordable responses"

ERGs were nonrecordable in 30 of 39 patients (77%), the FREQUENT band.

PMID:25268133 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"ERG showed no recordable pattern in four patients and could not be conducted in one patient."

Every Japanese patient tested had a nonrecordable ERG.

Constriction of peripheral visual field VERY_FREQUENT HP:0001133

Show evidence (2 references)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Peripheral visual field loss was reported in majority of patients (96%)."

Nearly all patients reported peripheral field loss.

PMID:41448483 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"VF impairment began in childhood and progressed to tunnel vision (VF ≤ 10°) at a median age of 39.4 years."

Quantifies the course of visual field constriction.

Spicular pigmentation of the retina VERY_FREQUENT HP:0007737

Show evidence (2 references)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"peripheral bone-spicule pigmentation was present in 90% (36/40)."

Bone-spicule pigment was seen in 36 of 40 patients with fundus photographs.

PMID:27391953 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"fundus examination of proband shows the typical RP appearance including paravascular bone spicule pigmentation, retinal pigmented epithelium atrophy, pale disc, and arteriolar constriction"

Family report documenting bone-spicule pigment with other typical fundus signs.

Optic disc pallor VERY_FREQUENT HP:0000543

Show evidence (1 reference)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Waxy pallor of the optic disc was present in 82.5% (33/40) of patients"

Disc pallor in 33 of 40 photographed patients.

Perifoveal ring of hyperautofluorescence FREQUENT HP:0030629

Show evidence (1 reference)

PMID:41448483 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"FAF imaging revealed a macular hyper-autofluorescent (hyperAF) ring in 73% of patients."

A hyperautofluorescent macular ring was present in 73% of the Chinese cohort.

Reduced visual acuity HP:0007663

Onset: ADULT

Show evidence (2 references)

PMID:41448483 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"BCVA remained stable (0.09 logMAR) until age of 30.7 years, followed by a progressive decline at 0.029 logMAR per year; by age of 72 years, 32% of patients had developed blindness (BCVA > 1.30 logMAR)."

Quantifies late-onset, slowly progressive acuity loss.

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Visual acuity decline was noted later, with a mean age at onset of 38.4 ± 13.5 years (n = 27)."

Subjective acuity decline began in the fourth decade on average.

Macular atrophy FREQUENT HP:0007401

Show evidence (1 reference)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"47.5% (19/40) showed frank signs of atrophy and pigmentary changes"

Macular atrophy in 19 of 40 photographed patients.

Epiretinal membrane FREQUENT HP:0100014

Show evidence (1 reference)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Epiretinal membranes were identified in 57.9% of eyes (66/114), affecting 63.2% of patients, with bilateral involvement observed in 83.3% of cases."

Epiretinal membrane affected 63% of patients.

Cystoid macular edema OCCASIONAL HP:0011505

Show evidence (1 reference)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"clinically significant cystoid macular edema (CME) involving the fovea was present in 12.3% (14/114)."

The figure is per eye, not per patient.

Cataract FREQUENT HP:0000518

Show evidence (2 references)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cataract (including pseudophakia) was highly prevalent, affecting 31 of 57 patients (54%)."

Cataract or prior cataract surgery in 54% of patients.

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Anterior subcapsular cataracts were identified in 7 patients while posterior subcapsular cataracts were identified in 5 patients."

Of 10 patients with morphology recorded, anterior subcapsular opacity was the more common type.

Myopia FREQUENT HP:0000545

Show evidence (1 reference)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Myopia was the most common refractive error (19/28, 67.9%), with 14.3% (4/28) classified as high myopia."

Myopia in 68% of patients with refraction data; the study had no population-matched comparison.

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Genetic Associations

1

CNGA1 (Causative)

Gene: CNGA1 hgnc:2148 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (4 references)

PMID:7479749 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Five mutant sequences cosegregated with disease among four unrelated families with autosomal recessive RP."

Gene-discovery evidence for CNGA1 as a causal arRP gene.

PMID:41448483 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"c.265delC was confirmed as a hotspot variant with an allele frequency of 72% in the Chinese population."

Identifies the predominant Chinese allele; the frequency is among patient alleles in the cohort.

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The c.253delC variant was the predominant mutation in both the Chinese and Korean cohorts, with an allele frequency of 69%."

The recurrent frameshift predominates in both Chinese and Korean patients.

+ 1 more reference

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Medical Actions

5

AAV-Mediated CNGA1 Gene Augmentation Therapy

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

Investigational. Subretinal AAV8-hRHO-mCnga1 restores rod function, reverses cGMP accumulation and preserves photoreceptors in the Cnga1 knockout mouse. An intravitreal AAV2.NN-CNGA1 vector (VG901) is in a phase 1b open-label safety study in patients. Human efficacy has not been established.

Mechanism Target:

RESTORES Loss of Rod Light Responses — Restores rod-mediated retinal function in the knockout mouse when given before major rod loss.

Show evidence (1 reference)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Gene augmentation therapy results in robust expression of correctly localized CNGA1 protein, sustained rescue of retinal function and long-term preservation of photoreceptors for at least 9 months."

Preclinical restoration of rod function and structure.

INHIBITS Rod cGMP Accumulation — Reverses abnormal cGMP accumulation in treated retina.

Show evidence (1 reference)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We found that this toxic accumulation was reversed in the treated retina, whereas cGMP levels remained high in untreated eyes"

Immunohistochemical reversal of cGMP accumulation.

Show evidence (3 references)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"To the best of our knowledge, this work demonstrates for the first time that a gene augmentation approach can restore vision and preserves photoreceptors in an animal model of CNGA1-RP."

Preclinical proof of concept for CNGA1 gene augmentation.

clinicaltrials:NCT06291935 SUPPORT DIRECT PRIMARY RESULT Other

"Participants will be administered a single intravitreal dose of VG901 into the most affected eye through a syringe and followed up for a year to monitor safety and efficacy."

Registered first-in-human study design; it reports no results.

PMID:42440411 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"OCT imaging demonstrated long-term preservation of the foveal ellipsoid zone until stage 4, indicating a broad therapeutic window."

Preserved foveal photoreceptors in stages 1 to 3 define a population that could be treated; this is natural-history data, not treatment efficacy.

Genetic counseling

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

Platform: Other

Counseling explains autosomal recessive recurrence, carrier testing of relatives once the familial CNGA1 variants are known, and eligibility for gene-specific trials.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"At conception, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."

General autosomal recessive retinitis pigmentosa recurrence risk, applicable to CNGA1 families.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Carrier testing for at-risk relatives requires prior identification of the RP- related pathogenic variants in the family."

Carrier testing depends on knowing the familial variants.

Low-vision rehabilitation

Action: Low-vision rehabilitation Ontology label: Rehabilitation NCIT:C15315

Platform: Other

Low-vision aids and mobility, vocational and independent-living support address visual disability. This is general retinitis pigmentosa supportive care and does not restore channel function.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields."

General retinitis pigmentosa guidance supports functional aids.

Carbonic anhydrase inhibition for cystoid macular edema

Action: Pharmacotherapy NCIT:C15986

Agent: acetazolamide CHEBI:27690 dorzolamide CHEBI:4702

Platform: Small molecule

Oral acetazolamide or topical dorzolamide may be used for retinitis pigmentosa-associated cystoid macular edema; response is variable and rebound can occur. This is complication-directed care without CNGA1-specific trial evidence.

Target Phenotypes: Cystoid macular edema HP:0011505

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Some therapeutic success has been reported with both systemic and topical carbonic anhydrase inhibitors ... however, rebound edema can occur with continued use"

General retinitis pigmentosa treatment synthesis.

Cataract surgery when visually significant

Action: Cataract Surgery NCIT:C157809

Platform: Surgery

Cataract is common in middle age and impairs acuity; extraction is considered when it contributes materially to visual loss, recognizing a higher risk of postoperative inflammation and macular edema in retinitis pigmentosa.

Show evidence (2 references)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Surgical extraction had been performed in 21 patients at a mean age of 53.6 ± 11.0 years."

Cataract extraction is common in CNGA1 patients.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Individuals with retinitis pigmentosa are at a greater-than-average risk for postoperative inflammation and induced CME."

General retinitis pigmentosa perioperative consideration.

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Diagnosis

4

Molecular genetic testing

An inherited retinal disease panel or exome identifies biallelic CNGA1 variants. Missense variants of uncertain significance may need functional data or segregation; a whole-gene deletion has been reported, so copy-number assessment is relevant.

diagnostic procedure NCIT:C18020

Results: Biallelic pathogenic or likely pathogenic CNGA1 variants in trans.

Show evidence (2 references)

PMID:25268133 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Whole exome sequencing of 30 arRP/spRP patients identified disease-causing gene mutations of CNGA1 (four patients)"

Exome sequencing identifies CNGA1 disease among unsolved arRP patients.

PMID:42192302 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Data mining revealed 86 missense CNGA1 variants - including three novel - most of them lacking functional data; 65.1% of the variants were initially classified as VUS."

Most CNGA1 missense variants are initially of uncertain significance, so interpretation needs functional support.

Full-field electroretinography

Full-field ERG documents a rod-cone pattern; responses are nonrecordable in most adults.

diagnostic procedure NCIT:C18020

Results: Severely reduced or nonrecordable scotopic responses, with relatively preserved but attenuated photopic responses in early disease.

Show evidence (1 reference)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Scotopic responses in these patients were severely reduced or nonrecordable, whereas photopic responses were relatively preserved, although attenuated."

Characteristic ERG pattern in CNGA1 patients with recordable responses.

Multimodal retinal imaging and perimetry

Ultra-widefield fundus autofluorescence can stage disease by the size and presence of the hyperautofluorescent ring; OCT tracks ellipsoid-zone width, epiretinal membrane and cystoid change; static perimetry was proposed as the most promising trial endpoint.

diagnostic procedure NCIT:C18020

Results: Hyperautofluorescent ring constricting with stage; ellipsoid-zone width declining over years.

Show evidence (2 references)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The FAF-based staging system provides a reliable framework for severity assessment and reveals stage-specific progression patterns, with no significant genotype-phenotype association observed."

Autofluorescence staging stratifies CNGA1 disease severity.

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Static perimetry appears to be the most promising primary endpoint for future clinical trials."

Perimetry is the proposed outcome measure.

Ophthalmic surveillance

General retinitis pigmentosa guidance recommends annual dilated examination and perimetry, with closer review for complications such as cystoid macular edema and cataract.

Eye Examination NCIT:C38060

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"and a full ophthalmoscopic examination with dilation are performed on an annual basis, with more frequent follow up for active complications such as cystoid macular edema."

General retinitis pigmentosa surveillance guidance.

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Progression

3

Childhood-onset night blindness

Age: Early childhood

Night blindness is the first symptom, with mean onset around 4 years in one cohort and childhood onset in 88% of another.

Show evidence (1 reference)

PMID:42440411 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Nyctalopia was the initial symptom in all patients (100%), with a mean age at onset of 4.4 ± 2.7 years."

Establishes early-childhood onset.

Progressive visual field constriction with preserved central acuity

Age: Childhood to fourth decade

Field loss begins in childhood and reaches tunnel vision at a median of about 39 years, while acuity remains stable until about 30 years.

Show evidence (2 references)

PMID:41448483 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Based on the quantitative data, VA loss in CNGA1-RP is late-onset and slow-progressing, whereas VF loss occurs earlier and more severely."

Field loss precedes acuity loss.

PMID:38705136 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Rod CNG channel-associated RP was demonstrated to be a slowly progressive disease in both CNGA1- and CNGB1-related forms"

An Italian cohort including 11 CNGA1 patients also found slow progression.

Central visual decline and complications

Age: Fourth decade onward

Acuity declines slowly from the fourth decade, with cataract, epiretinal membrane and macular atrophy contributing; about a third were blind by age 72 in the Chinese cohort.

Show evidence (1 reference)

PMID:41448483 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"BCVA remained stable (0.09 logMAR) until age of 30.7 years, followed by a progressive decline at 0.029 logMAR per year; by age of 72 years, 32% of patients had developed blindness (BCVA > 1.30 logMAR)."

Quantifies late acuity decline.

🔬

Clinical Trials

1

NCT06291935 PHASE_I RECRUITING

Phase 1b open-label, single-arm safety study of a single intravitreal dose of an AAV vector expressing CNGA1 (AAV2.NN-CNGA1, VG901) in patients with retinitis pigmentosa due to CNGA1 variants, with low- and high-dose cohorts followed for one year. Status as recorded on ClinicalTrials.gov in October 2026.

Show evidence (1 reference)

clinicaltrials:NCT06291935 SUPPORT DIRECT PRIMARY RESULT Other

"The goal of this phase 1 clinical trial is to learn about the safety and efficacy of a gene therapy, VG901, in patients with a rare disorder of the eye called Retinitis Pigmentosa."

Registry record of the first CNGA1 gene therapy trial.

🧫

Experimental Models

2

Patient-derived iPSC line SJTUGHi002-A (CNGA1 c.265delC homozygous) CELL_LINE

Induced pluripotent stem cell line reprogrammed from blood cells of a 36-year-old man with retinitis pigmentosa homozygous for the recurrent c.265delC frameshift. It is a resource for differentiating patient retinal cells; no retinal phenotype has yet been reported from it, so it is not linked to a mechanism node.

Organism

human NCBITaxon:9606

Publication

PMID:38340451

Show evidence (1 reference)

PMID:38340451 SUPPORT DIRECT PRIMARY RESULT In Vitro

"we established the human induced pluripotent stem cell line (iPSC) SJTUGHi002-A, generated from peripheral blood mononuclear cells of a 36-year-old male RP patient, who carried a homozygous frameshift variant in CNGA1 gene (c.265delC; p.L89Ffs*4)"

Describes the patient-derived line and its genotype.

Patient-derived iPSC line BTHBIOi001-A (CNGA1 p.R420Q homozygous) CELL_LINE

Induced pluripotent stem cell line from a woman with retinitis pigmentosa homozygous for the CNGA1 missense variant c.1621G>A (p.R420Q). Characterized for pluripotency only; no retinal phenotype has been reported.

Organism

human NCBITaxon:9606

Publication

PMID:40795580

Show evidence (1 reference)

PMID:40795580 SUPPORT DIRECT PRIMARY RESULT In Vitro

"a human iPSC line of a retinitis pigmentosa patient was generated, with the mutation of CNGA1 gene (homozygous c.1621G > A; p.R 420 > Q)"

Describes the patient-derived line and its genotype.

🐁

Animal Models

3

Cnga1 knockout mouse (CRISPR/Cas9)

CRISPR/Cas9 knockout with absent rod-driven ERG, a transient supernormal cone response and rapid photoreceptor degeneration that is nearly complete by 6 months. It degenerates faster than the Y509C point mutant and lacks a macula.

Species

Mouse

Genotype

Cnga1-/- (CRISPR/Cas9 frameshift deletion)

Publication

PMID:34418172

Pathograph links

Loss of Rod Light Responses recapitulates fidelity: high observes: cellular Rod-specific ERG responses are absent from one month.

Limitations: Mouse retina lacks a macula; a null allele does not represent every human missense allele.

Readouts

Scotopic rod-specific ERG b-wave

Direction: ABOLISHED

Interpretation: Absent response to the rod-specific flash indicates a nonfunctional rod system.

Show evidence (1 reference)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In contrast, the Cnga1-/- mice showed no response to the rod-specific flash at −2 log cd s m−2"

Direct ERG measurement of absent rod response.

Show evidence (1 reference)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"These observations suggest that the rod system is not functional in the Cnga1-/- mouse."

The knockout reproduces the primary functional defect.

Progressive Rod Photoreceptor Degeneration partially recapitulates fidelity: moderate observes: cellular Progressive TUNEL-positive photoreceptor loss with microglial activation and oxidative damage.

Limitations: Degeneration is much faster than in patients, whose central acuity is preserved for decades.

Show evidence (1 reference)

PMID:34418172 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Immunofluorescence and TUNEL staining showed progressive degeneration in rods and cones. Moreover, microglial activation and oxidative stress damage occurred in parallel."

Histological evidence of progressive photoreceptor death in the knockout.

Loss of Rod Light Responses rescues fidelity: moderate observes: cellular Subretinal AAV8-hRHO-mCnga1 at postnatal day 14 restores correctly localized CNGA1, rod-mediated ERG and vision-guided behaviour for at least 8.5 months.

Limitations: Species-matched murine Cnga1, treatment before major rod loss, and a fast-degenerating null background limit inference to older patients treated at later stages.

Readouts

Scotopic rod-specific ERG b-wave after treatment

Direction: RESTORED

Interpretation: A rod-specific ERG response appears in treated but not untreated eyes.

Show evidence (1 reference)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"At the ISCEV rod-specific flash of −2 log cd s m−2, the treated Cnga1-/- eye exhibited a clear positive b-wave, while the untreated Cnga1-/- eye did not show a response"

Direct ERG evidence of restored rod function.

Show evidence (1 reference)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Gene augmentation therapy results in robust expression of correctly localized CNGA1 protein, sustained rescue of retinal function and long-term preservation of photoreceptors for at least 9 months."

Gene augmentation rescues function and structure in the knockout.

Rod cGMP Accumulation rescues fidelity: moderate observes: molecular Treated retina loses the abnormal cGMP immunoreactivity seen in untreated eyes.

Limitations: Immunostaining is not a quantitative cGMP or calcium measurement.

Show evidence (1 reference)

PMID:40897815 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We found that this toxic accumulation was reversed in the treated retina, whereas cGMP levels remained high in untreated eyes"

Reversal of cGMP accumulation after gene augmentation.

Show evidence (1 reference)

PMID:34418172 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We observed progressive retinal thinning and a concomitant functional deficit in vivo as typical phenotypes for RP."

Establishes the knockout as a model of CNGA1 retinitis pigmentosa.

Cnga1 Y509C mouse (ENU-derived)

ENU-derived point mutation in the cyclic nucleotide-binding domain. CNGA1 and CNGB1 proteins are absent, rod-driven ERG is lost from postnatal week 3, and rods degenerate more slowly than in the knockout, followed by complete cone loss by 12 months.

Species

Mouse

Genotype

Cnga1 c.1526A>G (p.Tyr509Cys) homozygous

Publication

PMID:36115851

Pathograph links

Defective Rod CNG Channel Membrane Expression recapitulates fidelity: moderate observes: molecular Both channel subunits are lost from rod outer segments despite normal transcript levels.

Limitations: The mouse Y509C allele differs from the human G509R allele in the same domain; protein loss may not apply to every missense allele.

Show evidence (1 reference)

PMID:36115851 SUPPORT DIRECT PRIMARY RESULT Model Organism

"While Cngb1 mRNA levels were also unaffected, we could not detect any CNGB1 protein in Cnga1Y509C/Y509C at 1 month of age."

Loss of the partner subunit protein accompanies CNGA1 loss.

Secondary Cone Degeneration recapitulates fidelity: moderate observes: tissue Cone-mediated responses decline secondarily and cones are lost by 12 months.

Limitations: Mice lack a cone-dense fovea, so macular sparing in patients cannot be modelled.

Show evidence (1 reference)

PMID:36115851 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Over time, a gradual reduction of PNA signal was observed, revealing a loss of the outer segments of cones at PM9 and a complete loss of the cones at PM12"

Histology of delayed cone loss.

Show evidence (1 reference)

PMID:36115851 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Homozygous Cnga1 mice harboring a (ENSMUST00000087213.12) c.1526 A > G (p.Tyr509Cys) mutation showed progressive degeneration in the retinal photoreceptors from 8 weeks on."

Establishes the point-mutant model.

Shetland sheepdog with CNGA1 frameshift (progressive retinal atrophy)

Naturally occurring progressive retinal atrophy in one Shetland sheepdog family associated with a CNGA1 frameshift. Its retinal phenotype has not been characterized in detail, and other affected Shelties in the population did not carry the variant.

Species

Dog

Genotype

CNGA1 c.1752_1755delAACT (frameshift, exon 9)

Publication

PMID:26202106

Show evidence (1 reference)

PMID:26202106 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Sequencing of this gene identified a 4-bp deletion in exon 9 (c.1752_1755delAACT), leading to a frameshift and a premature stop codon."

Identifies the canine CNGA1 allele associated with progressive retinal atrophy.

{ }

Source YAML

click to show

name: CNGA1-Related Retinopathy
creation_date: "2026-10-14T15:02:40Z"
category: Mendelian
description: >-
  CNGA1-related retinopathy is an autosomal recessive rod-cone dystrophy (retinitis pigmentosa 49) caused by biallelic pathogenic variants in CNGA1, which encodes the alpha subunit of the cGMP-gated cation channel in the rod outer-segment plasma membrane. The rod channel is a heterotetramer of three CNGA1 subunits and one CNGB1 subunit and carries the dark current that light closes. Most reported alleles are truncating or frameshift variants; characterized missense alleles reduce channel abundance at the plasma membrane or impair channel function. Loss of the channel abolishes rod light responses, so night blindness typically begins in early childhood and the rod electroretinogram is severely reduced or nonrecordable. Rods then degenerate, producing progressive peripheral field constriction, bone-spicule pigmentation, vascular attenuation and optic disc pallor, followed by secondary cone loss. Central acuity is often preserved until the fourth decade, which has made the disease a candidate for gene augmentation. Epiretinal membrane, cystoid macular change and cataract are common accompanying findings. CNGA1 variants are an uncommon cause of autosomal recessive retinitis pigmentosa in the original North American screen but are more frequent in East Asian cohorts, where a recurrent frameshift allele predominates.
disease_term:
  preferred_term: CNGA1-related retinopathy
  term:
    id: MONDO:0800405
    label: CNGA1-related retinopathy
synonyms:
- Retinitis pigmentosa 49
- RP49
- CNGA1-associated retinitis pigmentosa
- CNGA1-related autosomal recessive retinitis pigmentosa
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0013405
      label: retinitis pigmentosa 49
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO places retinitis pigmentosa 49 (OMIM:613756, retinitis pigmentosa caused by mutation in CNGA1) as the single child of MONDO:0800405. All reported CNGA1 disease presents as autosomal recessive retinitis pigmentosa, so the subtype is captured as a mapping rather than a separate has_subtypes row.
notes: >-
  CNGA1 is distinct from CNGB1-related retinopathy (the partner rod channel subunit, curated separately as CNGB1-Related_Retinopathy) and from CNGA3/CNGB3 cone channel disease (achromatopsia). Findings from those genes are not used here as CNGA1 evidence; where a CNGA1 model shows loss of the CNGB1 partner protein, that is recorded as a CNGA1 finding. There is no GeneReviews chapter specific to CNGA1; the Nonsyndromic Retinitis Pigmentosa Overview supplies general retinitis pigmentosa diagnostic and management guidance. The recurrent East Asian frameshift is reported as c.265delC (p.L89Ffs) in studies using NM_000087.3 numbering and as c.253delC (p.Leu85Phefs*4) in a study annotated to NM_001379270.1.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    CNGA1-related retinopathy is caused by biallelic (homozygous or compound heterozygous) pathogenic CNGA1 variants. Heterozygous carriers are unaffected.
  evidence:
  - reference: PMID:7479749
    reference_title: Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Five mutant sequences cosegregated with disease among four unrelated families with autosomal recessive RP.
    explanation: The gene-discovery study found CNGA1 variants cosegregating with disease in autosomal recessive families.
  - reference: PMID:15570217
    reference_title: Autosomal recessive retinitis pigmentosa in a Pakistani family mapped to CNGA1 with identification of a novel mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The mutation is found in a homozygous state in all 7 affected individuals and was heterozygous in all 15 unaffected family members examined.
    explanation: Linkage and segregation in a consanguineous family show that homozygotes are affected and heterozygous carriers are not.
pathophysiology:
- name: Biallelic CNGA1 Loss of Function
  description: >-
    Biallelic pathogenic CNGA1 variants remove or disable the alpha subunit of the rod cGMP-gated channel. Early nonsense and frameshift alleles and whole-gene deletion are expected to encode no functional channel; missense and distal frameshift alleles that have been expressed in vitro reduce membrane targeting, abundance or channel function. Not every reported missense variant is pathogenic, and functional testing has reclassified many variants of uncertain significance.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  role: trigger
  gene:
    preferred_term: CNGA1
    term:
      id: hgnc:2148
      label: CNGA1
    modifier: DECREASED
  genetic_context:
    gene:
      preferred_term: CNGA1
      term:
        id: hgnc:2148
        label: CNGA1
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline CNGA1 variants, homozygous or compound heterozygous; most are truncating, with a smaller set of missense alleles shown to impair channel expression or function.
  conforms_to: phototransduction_cascade_dysfunction#Phototransduction Cascade Component Defect
  molecular_functions:
  - preferred_term: cGMP-gated cation channel activity
    term:
      id: GO:0005223
      label: intracellularly cGMP-activated cation channel activity
    modifier: DECREASED
  evidence:
  - reference: PMID:7479749
    reference_title: Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Two of these were nonsense mutations early in the reading frame (Glu76End and Lys139End) and one was a deletion encompassing most if not all of the transcriptional unit; these three alleles would not be expected to encode a functional channel.
    explanation: The original patient alleles include early nonsense variants and a whole-gene deletion predicted to abolish the channel.
  - reference: PMID:25268133
    reference_title: Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Consequently, three CNGA1 frameshift mutations (c.191delG, c.265delC and c.1429delG) were identified as arRP-causing mutations in five patients
    explanation: All causal alleles in the Japanese cohort were frameshifts removing functional domains of the channel.
  - reference: PMID:42192302
    reference_title: Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The aequorin-based assay showed that 72.1% of tested variants significantly impaired CNG channel function and were classified as functionally abnormal, while 23.3% were functionally normal and 5% remained functionally uncertain.
    explanation: A functional screen of disease-associated missense variants shows that most impair channel function while a minority behave normally, so missense alleles need functional or segregation support.
  downstream:
  - target: Defective Rod CNG Channel Membrane Expression
    description: Loss or misfolding of CNGA1 prevents assembly or surface delivery of the heteromeric rod channel.
    causal_link_type: DIRECT
- name: Defective Rod CNG Channel Membrane Expression
  description: >-
    The native rod channel is a 3:1 CNGA1:CNGB1 heterotetramer in the outer-segment plasma membrane. Mutant CNGA1 proteins expressed in vitro are retained inside the cell or reach the membrane at reduced levels, and one C-terminal frameshift abolishes surface expression only when coexpressed with CNGB1. In a Cnga1 point-mutant mouse, CNGA1 protein is lost and the CNGB1 partner protein is also undetectable despite normal transcript levels, so the outer segment lacks the channel complex.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  cellular_components:
  - preferred_term: photoreceptor outer segment
    term:
      id: GO:0001750
      label: photoreceptor outer segment
  molecular_functions:
  - preferred_term: cGMP-gated cation channel activity
    term:
      id: GO:0005223
      label: intracellularly cGMP-activated cation channel activity
    modifier: DECREASED
  evidence:
  - reference: PMID:7479749
    reference_title: Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The latter two mutations were expressed in vitro and found to encode proteins that were predominantly retained inside the cell instead of being targeted to the plasma membrane.
    explanation: Heterologous expression of the Ser316Phe and Arg654 frameshift alleles shows failure of plasma membrane targeting.
  - reference: PMID:11970862
    reference_title: An intersubunit interaction regulates trafficking of rod cyclic nucleotide-gated channels and is disrupted in an inherited form of blindness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: As native retinal rod CNG channels comprise CNGA1 and CNGB1 subunits, we coexpressed CNGA1-RP and CNGB1. Surprisingly, this subunit combination did not produce detectable channels at the membrane surface.
    explanation: In Xenopus oocytes the disease-associated CNGA1 truncation forms normal homomers but prevents surface expression of the native-type heteromer with CNGB1.
  - reference: PMID:26802146
    reference_title: Novel compound heterozygous mutation in the CNGA1 gene underlie autosomal recessive retinitis pigmentosa in a Chinese family.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The mut CNGA1 p.(G513R) protein was largely retained inside the cell rather than being targeted to the plasma membrane
    explanation: A patient missense allele in the cyclic nucleotide-binding domain is retained intracellularly in vitro.
  - reference: PMID:30652268
    reference_title: A Novel CNGA1 Gene Mutation (c.G622A) of Autosomal Recessive Retinitis Pigmentosa Leads to the CNGA1 Protein Reduction on Membrane.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: western blot and immunofluorescence results indicated that the expression of mutant CNGA1 (D208N) decreased significantly, especially on the membrane of transfected HEK293T cells.
    explanation: A second patient missense allele reduces CNGA1 abundance at the plasma membrane of HEK293T cells.
  - reference: PMID:36115851
    reference_title: Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: While Cngb1 mRNA levels were also unaffected, we could not detect any CNGB1 protein in Cnga1Y509C/Y509C at 1 month of age.
    explanation: In the Cnga1 Y509C mouse, loss of CNGA1 protein is accompanied by loss of the CNGB1 partner protein, so the rod lacks the whole channel complex.
  - reference: PMID:34699778
    reference_title: Structural mechanisms of assembly, permeation, gating, and pharmacology of native human rod CNG channel.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: However, the native rod CNG functions as a heterotetramer consisting of three A1 and one B1 subunits and exhibits different functional properties than the CNGA1 homomer.
    explanation: Establishes the 3:1 CNGA1:CNGB1 composition of the native human rod channel that CNGA1 loss removes.
  downstream:
  - target: Loss of Rod Light Responses
    description: Without outer-segment cGMP-gated channels, light-driven closure of the dark current cannot generate a rod response.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37054604
      reference_title: CNG channel-related retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The rod CNG channel is expressed in the plasma membrane of the outer segment and functions as a molecular switch that converts light-mediated changes in cGMP into a voltage and Ca2+ signal.
      explanation: The channel is the final transduction element, so its absence removes the electrical light response of the rod.
- name: Loss of Rod Light Responses
  description: >-
    Rods lacking CNGA1 channels do not generate light responses. In Cnga1 knockout and Cnga1 Y509C mice, rod-driven ERG responses are absent from the earliest recordings, before extensive photoreceptor loss. In patients, scotopic ERG responses are severely reduced or nonrecordable.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  conforms_to: phototransduction_cascade_dysfunction#Failure of Photoreceptor Light-Response Generation or Timely Recovery
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: phototransduction
    term:
      id: GO:0007602
      label: phototransduction
    modifier: DECREASED
  evidence:
  - reference: PMID:40897815
    reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These observations suggest that the rod system is not functional in the Cnga1-/- mouse.
    explanation: Scotopic ERGs in the knockout lack a rod-specific response and rod-derived a-wave components.
  - reference: PMID:36115851
    reference_title: Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Consistent with the loss of rod CNG channel function, we observed an absence of rod-driven ERG responses (a- and b-wave) from the earliest observation time point (PW3).
    explanation: An independent point-mutant model shows absent rod-driven responses from postnatal week 3.
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Scotopic responses in these patients were severely reduced or nonrecordable, whereas photopic responses were relatively preserved, although attenuated.
    explanation: In the minority of patients with recordable ERGs, the rod system is disproportionately affected.
  downstream:
  - target: Rod cGMP Accumulation
    description: Channel-deficient rods accumulate cGMP; gene augmentation reverses this in treated retina.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Progressive Rod Photoreceptor Degeneration
    description: Loss of rod function precedes progressive rod death in CNGA1-deficient mice; the intermediates connecting channel loss to death are not fully resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40897815
      reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Cnga1-/- mice have a similar phenotype to human patients, characterized by an early loss of rod-mediated retinal function and progressive photoreceptor degeneration, which is nearly complete by 6 months of age.
      explanation: The temporal order in the knockout is early rod functional loss followed by progressive photoreceptor degeneration.
  - target: Nyctalopia
    description: Loss of rod-mediated vision impairs vision in dim light.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: In RP , loss of rod function predominates early in the clinical course. The initial symptom of RP is usually defective dark adaptation
      explanation: General retinitis pigmentosa physiology links early rod dysfunction with defective dark adaptation; CNGA1 cohorts establish night blindness as the first symptom.
  - target: Undetectable electroretinogram
    description: Loss of the rod light response removes the rod-driven ERG; later cone loss extinguishes the remaining photopic response.
    causal_link_type: DIRECT
- name: Rod cGMP Accumulation
  description: >-
    Untreated Cnga1-/- retina shows abnormally high cGMP immunoreactivity, and AAV-mediated CNGA1 expression reverses it in treated regions. The study describes the accumulation as a feature of impaired CNG channel function that triggers photoreceptor death, citing other work; the death-effector pathway was not measured in CNGA1 models.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  conforms_to: phototransduction_cascade_dysfunction#Loss of Outer-Segment cGMP and Calcium Set-Point Control
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  evidence:
  - reference: PMID:40897815
    reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We found that this toxic accumulation was reversed in the treated retina, whereas cGMP levels remained high in untreated eyes
    explanation: Immunohistochemistry shows high cGMP in untreated Cnga1-/- retina and its reversal after CNGA1 gene augmentation.
  downstream:
  - target: Progressive Rod Photoreceptor Degeneration
    description: Abnormal cGMP accumulation is proposed to contribute to rod death; the causal step has not been isolated in CNGA1 models.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40897815
      reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: A major feature of impaired CNG channel function is the abnormal concentration of cGMP1, which triggers photoreceptor death2,37.
      explanation: The authors frame cGMP accumulation as a death trigger with reference to prior work; it is a background claim rather than a CNGA1-specific experiment.
- name: Progressive Rod Photoreceptor Degeneration
  description: >-
    Rods degenerate after loss of function. In the CRISPR Cnga1 knockout the outer nuclear layer thins almost linearly and is nearly gone by 6 months, with TUNEL-positive photoreceptors, microglial activation and oxidative damage, and transcriptomic evidence of reduced PI3K-AKT-mTOR signalling with chaperone-mediated autophagy coinciding with photoreceptor death. The Y509C point mutant degenerates more slowly. In patients, ellipsoid-zone width declines over years and fundus changes of retinitis pigmentosa accumulate.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  conforms_to: photoreceptor_degeneration#Rod Photoreceptor Apoptosis
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: microglial cell activation
    term:
      id: GO:0001774
      label: microglial cell activation
    modifier: INCREASED
  - preferred_term: chaperone-mediated autophagy
    term:
      id: GO:0061684
      label: chaperone-mediated autophagy
    modifier: INCREASED
  evidence:
  - reference: PMID:34418172
    reference_title: Retinal degeneration in mice lacking the cyclic nucleotide-gated channel subunit CNGA1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Immunofluorescence and TUNEL staining showed progressive degeneration in rods and cones. Moreover, microglial activation and oxidative stress damage occurred in parallel.
    explanation: The knockout shows progressive TUNEL-positive photoreceptor degeneration with concurrent microglial activation and oxidative damage; the order of these events is not resolved.
  - reference: PMID:34418172
    reference_title: Retinal degeneration in mice lacking the cyclic nucleotide-gated channel subunit CNGA1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: In addition, the down-regulated PI3K-AKT-mTOR pathway indicated upregulation of autophagic process, and chaperone-mediated autophagy was further shown to coincide with the time course of photoreceptor death.
    explanation: Chaperone-mediated autophagy coincides with photoreceptor death; whether it drives or responds to degeneration is not established.
  - reference: PMID:40897815
    reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The thickness of ONL reduced to 46% of the wild-type at the age of 3 months and became hardly discernible by the age of 6 months
    explanation: OCT quantifies progressive photoreceptor nuclear layer loss in the knockout.
  - reference: PMID:36115851
    reference_title: Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Homozygous Cnga1 mice harboring a (ENSMUST00000087213.12) c.1526 A > G (p.Tyr509Cys) mutation showed progressive degeneration in the retinal photoreceptors from 8 weeks on.
    explanation: A point-mutant model also shows progressive photoreceptor degeneration, at a slower rate than the knockout.
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In stage-stratified mixed-effects models, stages 1 through 3 were best described by linear trends, with estimated declines of 88.6, 52.8, and 60.2 μm/year, respectively
    explanation: Longitudinal OCT measures progressive loss of ellipsoid-zone width, a structural marker of surviving photoreceptors, in patients.
  downstream:
  - target: Secondary Cone Degeneration
    description: Cone function and structure decline after rod loss; the non-cell-autonomous intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36115851
      reference_title: Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In summary, ERG analysis indicates a lack of rod photoreceptor-driven responses in Cnga1 mutant mice as early as PW3 and reveals a secondary, slowly progressive loss of cone-mediated light responses, leading to complete blindness after PM9.
      explanation: Cone-mediated responses decline secondarily and later than the primary rod defect.
  - target: Constriction of peripheral visual field
    description: Progressive loss of peripheral photoreceptors narrows the visual field.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37054604
      reference_title: CNG channel-related retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The loss of rod function is followed by a decline of photoreceptors due to progressive cell death, resulting in a gradual narrowing of the visual field.
      explanation: The CNG channel review states that progressive photoreceptor death produces visual field narrowing.
  - target: Spicular pigmentation of the retina
    description: Pigment migrates into the degenerating retina and clumps in a bone-spicule pattern as photoreceptors are lost.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: As photoreceptor deterioration progresses, there is increasing loss of pigment from the pigment epithelium with intraretinal clumping of melanin, appearing most often as coarse clumps in a "bone spicule" configuration.
      explanation: General retinitis pigmentosa pathology ties bone-spicule pigment to progressive photoreceptor deterioration.
  - target: Attenuation of retinal blood vessels
    description: Retinal vessel attenuation is a secondary change of long-standing retinal degeneration.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: The cause of the retinal vessel attenuation is unknown, but it appears to be a secondary change and not the primary cause of disease.
      explanation: General retinitis pigmentosa guidance treats vessel attenuation as secondary to the degeneration, with an unknown mechanism.
  - target: Optic disc pallor
    description: Waxy disc pallor reflects long-standing retinal degeneration.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: These changes reflect long-standing retinal degeneration and need not be present to make the diagnosis of RP .
      explanation: The preceding sentence of the overview lists pigment clumps, attenuated vessels, RPE loss and optic nerve pallor, all described as consequences of long-standing degeneration.
- name: Secondary Cone Degeneration
  description: >-
    Cones degenerate after rod loss. In the knockout, cone-mediated ERG responses pass through a transient supernormal phase and then decline with cone morphology compromised; in the Y509C mouse, cone outer segments are lost by 9 months and cones by 12 months. In patients, central acuity is usually preserved for decades before declining, and advanced disease involves the whole retina.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  conforms_to: photoreceptor_degeneration#Secondary Cone Degeneration and Outer Retinal Thinning
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  evidence:
  - reference: PMID:40897815
    reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In summary, the ERG analysis indicates a lack of rod-driven response in the Cnga1-/- mouse, and reveals a progressive loss of cone-mediated function with an initial 'supernormal' phase.
    explanation: Cone function in the knockout declines progressively after an early supernormal period.
  - reference: PMID:36115851
    reference_title: Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Over time, a gradual reduction of PNA signal was observed, revealing a loss of the outer segments of cones at PM9 and a complete loss of the cones at PM12
    explanation: Histology shows delayed but complete cone loss in the point-mutant model.
  - reference: PMID:25268133
    reference_title: Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: Retinal degeneration in the macular region and severely decreased BCVA occurred in 3/5 patients suggesting that the advanced stage of CNGA1 mutations included degeneration of the entire retina with both rod and cone photoreceptors.
    explanation: Macular degeneration and reduced acuity in advanced patients indicate cone involvement; the inference to cone loss is the authors' interpretation of clinical findings.
  downstream:
  - target: Rod-cone dystrophy
    description: Rod-first, cone-second degeneration produces the rod-cone dystrophy pattern.
    causal_link_type: DIRECT
  - target: Reduced visual acuity
    description: Loss of central cone function reduces visual acuity, usually after the third decade; cataract and macular complications also contribute.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Macular atrophy
    description: Advanced disease extends to the macula with atrophic and pigmentary changes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Undetectable electroretinogram
    description: Loss of cones removes the residual photopic response, leaving a nonrecordable ERG in most adult patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Ophthalmological
  name: Nyctalopia
  frequency: VERY_FREQUENT
  description: >-
    Night blindness is the first symptom in essentially all patients and usually begins in early childhood. In the East Asian cohort mean onset was 4.4 years; in the Chinese natural-history cohort 88% had childhood onset.
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Nyctalopia was the initial symptom in all patients (100%), with a mean age at onset of 4.4 ± 2.7 years.
    explanation: Night blindness was universal and of early-childhood onset in 57 East Asian patients.
  - reference: PMID:41448483
    reference_title: Natural History of CNGA1-Associated Retinitis Pigmentosa in a Large Chinese Cohort Revealing an Optimal Intervention Window.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Night blindness was the universal initial symptom, with most patients (88%) experiencing onset during childhood.
    explanation: A separate 58-patient Chinese cohort confirms night blindness as the universal presenting symptom.
  - reference: PMID:25268133
    reference_title: Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All five patients reported that they noticed night blindness from childhood.
    explanation: Childhood night blindness in every Japanese patient with biallelic CNGA1 variants.
- category: Ophthalmological
  name: Rod-cone dystrophy
  frequency: VERY_FREQUENT
  description: >-
    Electroretinography shows a rod-cone pattern, with rod responses lost first and cone responses attenuated later.
  phenotype_term:
    preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Consistent with a diagnosis of RP, all patients exhibited rod-cone dysfunction with high interocular symmetry
    explanation: All 39 patients with full-field ERG had rod-cone dysfunction.
- category: Ophthalmological
  name: Undetectable electroretinogram
  frequency: FREQUENT
  description: >-
    Full-field ERG is nonrecordable in most patients by adulthood; residual responses, when present, are mostly cone-mediated and occur in younger patients with earlier-stage disease.
  phenotype_term:
    preferred_term: Nonrecordable full-field electroretinogram
    term:
      id: HP:0000550
      label: Undetectable electroretinogram
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Residual responses were detected in only 9 of 39 patients (23%), and these patients were significantly younger than those with nonrecordable responses
    explanation: ERGs were nonrecordable in 30 of 39 patients (77%), the FREQUENT band.
  - reference: PMID:25268133
    reference_title: Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: ERG showed no recordable pattern in four patients and could not be conducted in one patient.
    explanation: Every Japanese patient tested had a nonrecordable ERG.
- category: Ophthalmological
  name: Constriction of peripheral visual field
  frequency: VERY_FREQUENT
  description: >-
    Peripheral field loss begins in childhood and progresses; in the Chinese natural-history cohort tunnel vision (10 degrees or less) was reached at a median age of 39.4 years.
  phenotype_term:
    preferred_term: Constriction of peripheral visual field
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Peripheral visual field loss was reported in majority of patients (96%).
    explanation: Nearly all patients reported peripheral field loss.
  - reference: PMID:41448483
    reference_title: Natural History of CNGA1-Associated Retinitis Pigmentosa in a Large Chinese Cohort Revealing an Optimal Intervention Window.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: VF impairment began in childhood and progressed to tunnel vision (VF ≤ 10°) at a median age of 39.4 years.
    explanation: Quantifies the course of visual field constriction.
- category: Ophthalmological
  name: Spicular pigmentation of the retina
  frequency: VERY_FREQUENT
  description: >-
    Peripheral bone-spicule pigmentation is present in most patients, though it can be absent in early disease despite vascular attenuation.
  phenotype_term:
    preferred_term: Bone-spicule pigmentation of the retina
    term:
      id: HP:0007737
      label: Spicular pigmentation of the retina
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: peripheral bone-spicule pigmentation was present in 90% (36/40).
    explanation: Bone-spicule pigment was seen in 36 of 40 patients with fundus photographs.
  - reference: PMID:27391953
    reference_title: Novel compound heterozygous mutations in CNGA1in a Chinese family affected with autosomal recessive retinitis pigmentosa by targeted sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: fundus examination of proband shows the typical RP appearance including paravascular bone spicule pigmentation, retinal pigmented epithelium atrophy, pale disc, and arteriolar constriction
    explanation: Family report documenting bone-spicule pigment with other typical fundus signs.
- category: Ophthalmological
  name: Attenuation of retinal blood vessels
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Attenuation of retinal blood vessels
    term:
      id: HP:0007843
      label: Attenuation of retinal blood vessels
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Fundus photography (40 patients available) revealed generalized vascular attenuation in all eyes.
    explanation: Vascular attenuation was universal among photographed patients.
  - reference: PMID:25268133
    reference_title: Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Funduscopy showed retinal degeneration with pigmentation and attenuation of retinal vessels in all patients
    explanation: Present in all five Japanese patients.
- category: Ophthalmological
  name: Optic disc pallor
  frequency: VERY_FREQUENT
  description: Waxy pallor of the optic disc.
  phenotype_term:
    preferred_term: Waxy optic disc pallor
    term:
      id: HP:0000543
      label: Optic disc pallor
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Waxy pallor of the optic disc was present in 82.5% (33/40) of patients
    explanation: Disc pallor in 33 of 40 photographed patients.
- category: Ophthalmological
  name: Perifoveal ring of hyperautofluorescence
  frequency: FREQUENT
  description: >-
    Fundus autofluorescence commonly shows a macular hyperautofluorescent ring bounding the preserved central retina. Ring constriction and its eventual disappearance were used to stage disease severity in the East Asian cohort.
  phenotype_term:
    preferred_term: Macular hyperautofluorescent ring
    term:
      id: HP:0030629
      label: Perifoveal ring of hyperautofluorescence
  evidence:
  - reference: PMID:41448483
    reference_title: Natural History of CNGA1-Associated Retinitis Pigmentosa in a Large Chinese Cohort Revealing an Optimal Intervention Window.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: FAF imaging revealed a macular hyper-autofluorescent (hyperAF) ring in 73% of patients.
    explanation: A hyperautofluorescent macular ring was present in 73% of the Chinese cohort.
- category: Ophthalmological
  name: Reduced visual acuity
  description: >-
    Central acuity is typically preserved into adulthood and declines from about the fourth decade. In the Chinese cohort acuity was stable until about 30.7 years and then declined by 0.029 logMAR per year, with 32% blind by age 72. Cataract contributes to acuity loss in the fourth and fifth decades.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
    onset:
      onset_category: ADULT
  evidence:
  - reference: PMID:41448483
    reference_title: Natural History of CNGA1-Associated Retinitis Pigmentosa in a Large Chinese Cohort Revealing an Optimal Intervention Window.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: BCVA remained stable (0.09 logMAR) until age of 30.7 years, followed by a progressive decline at 0.029 logMAR per year; by age of 72 years, 32% of patients had developed blindness (BCVA > 1.30 logMAR).
    explanation: Quantifies late-onset, slowly progressive acuity loss.
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Visual acuity decline was noted later, with a mean age at onset of 38.4 ± 13.5 years (n = 27).
    explanation: Subjective acuity decline began in the fourth decade on average.
- category: Ophthalmological
  name: Macular atrophy
  frequency: FREQUENT
  description: Macular findings are heterogeneous; nearly half of photographed patients show frank macular atrophy and pigmentary change, mainly in advanced disease.
  phenotype_term:
    preferred_term: Macular atrophy
    term:
      id: HP:0007401
      label: Macular atrophy
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 47.5% (19/40) showed frank signs of atrophy and pigmentary changes
    explanation: Macular atrophy in 19 of 40 photographed patients.
- category: Ophthalmological
  name: Epiretinal membrane
  frequency: FREQUENT
  description: Epiretinal membranes are common on OCT, often bilateral and foveal, and become more prevalent with disease stage.
  phenotype_term:
    preferred_term: Epiretinal membrane
    term:
      id: HP:0100014
      label: Epiretinal membrane
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Epiretinal membranes were identified in 57.9% of eyes (66/114), affecting 63.2% of patients, with bilateral involvement observed in 83.3% of cases.
    explanation: Epiretinal membrane affected 63% of patients.
- category: Ophthalmological
  name: Cystoid macular edema
  frequency: OCCASIONAL
  description: >-
    Clinically significant foveal cystoid macular edema occurred in about 12% of eyes, with additional minor inner nuclear layer cystoid spaces in about 14%. Macular edema was absent in a small Japanese series.
  phenotype_term:
    preferred_term: Cystoid macular edema
    term:
      id: HP:0011505
      label: Cystoid macular edema
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: clinically significant cystoid macular edema (CME) involving the fovea was present in 12.3% (14/114).
    explanation: The figure is per eye, not per patient.
- category: Ophthalmological
  name: Cataract
  frequency: FREQUENT
  description: >-
    Cataract is common from the fourth to fifth decade (mean age at diagnosis 47 years). Where morphology was recorded, anterior subcapsular opacity was more frequent than the posterior subcapsular cataract typical of retinitis pigmentosa in general.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cataract (including pseudophakia) was highly prevalent, affecting 31 of 57 patients (54%).
    explanation: Cataract or prior cataract surgery in 54% of patients.
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Anterior subcapsular cataracts were identified in 7 patients while posterior subcapsular cataracts were identified in 5 patients.
    explanation: Of 10 patients with morphology recorded, anterior subcapsular opacity was the more common type.
- category: Ophthalmological
  name: Myopia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Myopia was the most common refractive error (19/28, 67.9%), with 14.3% (4/28) classified as high myopia.
    explanation: Myopia in 68% of patients with refraction data; the study had no population-matched comparison.
genetic:
- name: CNGA1
  gene_term:
    preferred_term: CNGA1
    term:
      id: hgnc:2148
      label: CNGA1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Causative
  features: >-
    Reported causal alleles are mostly frameshift and nonsense variants, plus a whole-gene deletion and missense variants. In East Asian cohorts a single recurrent frameshift accounts for most alleles (72% of patient alleles in a Chinese cohort, 69% in a Chinese and Korean cohort); the Chinese study found a more severe phenotype in homozygotes, while the East Asian study found no significant genotype-phenotype association. A functional screen of 86 missense variants classified most as functionally abnormal and allowed reclassification of many variants of uncertain significance.
  case_fractions:
  - population: Japanese patients with autosomal recessive or sporadic retinitis pigmentosa
    case_fraction_percent: 5.1
    cohort_size: 99
    notes: Five of 99 unrelated patients carried biallelic CNGA1 frameshift variants.
    evidence:
    - reference: PMID:25268133
      reference_title: Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The frequency of CNGA1 gene mutation was 5.1% (5/99 patients).
      explanation: Primary estimate of the CNGA1 share of arRP and sporadic RP in Japan.
  - population: Autosomal recessive retinitis pigmentosa patients screened in the gene-discovery study
    case_fraction_low: 1.7
    case_fraction_high: 2.3
    cohort_size: 173
    notes: Three or four of 173 unrelated arRP patients, as restated by a later study; the original paper described CNGA1 as an uncommon cause of RP.
    evidence:
    - reference: PMID:25268133
      reference_title: Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: DIRECT
      snippet: Dryja et al. estimated the prevalence of CNGA1 mutations in arRP patients to be between 1.7 and 2.3% (3 or 4 of 173 patients)
      explanation: Restates the case fraction implied by the gene-discovery screen.
    - reference: PMID:7479749
      reference_title: Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We conclude that the absence or paucity of functional cGMP-gated cation channels in the plasma membrane is deleterious to rod photoreceptors and is an uncommon cause of RP.
      explanation: The original screen concluded that CNGA1 is an uncommon cause of RP.
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:15570217
      reference_title: Autosomal recessive retinitis pigmentosa in a Pakistani family mapped to CNGA1 with identification of a novel mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The autosomal recessive retinitis pigmentosa in this family is caused by a mutation in CNGA1 gene.
      explanation: Linkage plus a homozygous frameshift establishes recessive CNGA1 disease.
  evidence:
  - reference: PMID:7479749
    reference_title: Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Five mutant sequences cosegregated with disease among four unrelated families with autosomal recessive RP.
    explanation: Gene-discovery evidence for CNGA1 as a causal arRP gene.
  - reference: PMID:41448483
    reference_title: Natural History of CNGA1-Associated Retinitis Pigmentosa in a Large Chinese Cohort Revealing an Optimal Intervention Window.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: c.265delC was confirmed as a hotspot variant with an allele frequency of 72% in the Chinese population.
    explanation: Identifies the predominant Chinese allele; the frequency is among patient alleles in the cohort.
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The c.253delC variant was the predominant mutation in both the Chinese and Korean cohorts, with an allele frequency of 69%.
    explanation: The recurrent frameshift predominates in both Chinese and Korean patients.
  - reference: PMID:42192302
    reference_title: Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Based on the functional findings, 62.1% of the variants initially classified as VUS were re-categorized as likely pathogenic or likely benign.
    explanation: Functional data resolve many CNGA1 missense variants of uncertain significance.
animal_models:
- name: Cnga1 knockout mouse (CRISPR/Cas9)
  species: Mouse
  genotype: Cnga1-/- (CRISPR/Cas9 frameshift deletion)
  publication: PMID:34418172
  description: >-
    CRISPR/Cas9 knockout with absent rod-driven ERG, a transient supernormal cone response and rapid photoreceptor degeneration that is nearly complete by 6 months. It degenerates faster than the Y509C point mutant and lacks a macula.
  evidence:
  - reference: PMID:34418172
    reference_title: Retinal degeneration in mice lacking the cyclic nucleotide-gated channel subunit CNGA1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We observed progressive retinal thinning and a concomitant functional deficit in vivo as typical phenotypes for RP.
    explanation: Establishes the knockout as a model of CNGA1 retinitis pigmentosa.
  modeled_mechanisms:
  - target: Loss of Rod Light Responses
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Rod-specific ERG responses are absent from one month.
    limitations: Mouse retina lacks a macula; a null allele does not represent every human missense allele.
    readouts:
    - name: Scotopic rod-specific ERG b-wave
      target: Loss of Rod Light Responses
      direction: ABOLISHED
      interpretation: Absent response to the rod-specific flash indicates a nonfunctional rod system.
      evidence:
      - reference: PMID:40897815
        reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: In contrast, the Cnga1-/- mice showed no response to the rod-specific flash at −2 log cd s m−2
        explanation: Direct ERG measurement of absent rod response.
    evidence:
    - reference: PMID:40897815
      reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: These observations suggest that the rod system is not functional in the Cnga1-/- mouse.
      explanation: The knockout reproduces the primary functional defect.
  - target: Progressive Rod Photoreceptor Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Progressive TUNEL-positive photoreceptor loss with microglial activation and oxidative damage.
    limitations: Degeneration is much faster than in patients, whose central acuity is preserved for decades.
    evidence:
    - reference: PMID:34418172
      reference_title: Retinal degeneration in mice lacking the cyclic nucleotide-gated channel subunit CNGA1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Immunofluorescence and TUNEL staining showed progressive degeneration in rods and cones. Moreover, microglial activation and oxidative stress damage occurred in parallel.
      explanation: Histological evidence of progressive photoreceptor death in the knockout.
  - target: Loss of Rod Light Responses
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Subretinal AAV8-hRHO-mCnga1 at postnatal day 14 restores correctly localized CNGA1, rod-mediated ERG and vision-guided behaviour for at least 8.5 months.
    limitations: Species-matched murine Cnga1, treatment before major rod loss, and a fast-degenerating null background limit inference to older patients treated at later stages.
    readouts:
    - name: Scotopic rod-specific ERG b-wave after treatment
      target: Loss of Rod Light Responses
      direction: RESTORED
      interpretation: A rod-specific ERG response appears in treated but not untreated eyes.
      evidence:
      - reference: PMID:40897815
        reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: At the ISCEV rod-specific flash of −2 log cd s m−2, the treated Cnga1-/- eye exhibited a clear positive b-wave, while the untreated Cnga1-/- eye did not show a response
        explanation: Direct ERG evidence of restored rod function.
    evidence:
    - reference: PMID:40897815
      reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Gene augmentation therapy results in robust expression of correctly localized CNGA1 protein, sustained rescue of retinal function and long-term preservation of photoreceptors for at least 9 months.
      explanation: Gene augmentation rescues function and structure in the knockout.
  - target: Rod cGMP Accumulation
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Treated retina loses the abnormal cGMP immunoreactivity seen in untreated eyes.
    limitations: Immunostaining is not a quantitative cGMP or calcium measurement.
    evidence:
    - reference: PMID:40897815
      reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We found that this toxic accumulation was reversed in the treated retina, whereas cGMP levels remained high in untreated eyes
      explanation: Reversal of cGMP accumulation after gene augmentation.
- name: Cnga1 Y509C mouse (ENU-derived)
  species: Mouse
  genotype: Cnga1 c.1526A>G (p.Tyr509Cys) homozygous
  publication: PMID:36115851
  description: >-
    ENU-derived point mutation in the cyclic nucleotide-binding domain. CNGA1 and CNGB1 proteins are absent, rod-driven ERG is lost from postnatal week 3, and rods degenerate more slowly than in the knockout, followed by complete cone loss by 12 months.
  evidence:
  - reference: PMID:36115851
    reference_title: Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Homozygous Cnga1 mice harboring a (ENSMUST00000087213.12) c.1526 A > G (p.Tyr509Cys) mutation showed progressive degeneration in the retinal photoreceptors from 8 weeks on.
    explanation: Establishes the point-mutant model.
  modeled_mechanisms:
  - target: Defective Rod CNG Channel Membrane Expression
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Both channel subunits are lost from rod outer segments despite normal transcript levels.
    limitations: The mouse Y509C allele differs from the human G509R allele in the same domain; protein loss may not apply to every missense allele.
    evidence:
    - reference: PMID:36115851
      reference_title: Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: While Cngb1 mRNA levels were also unaffected, we could not detect any CNGB1 protein in Cnga1Y509C/Y509C at 1 month of age.
      explanation: Loss of the partner subunit protein accompanies CNGA1 loss.
  - target: Secondary Cone Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Cone-mediated responses decline secondarily and cones are lost by 12 months.
    limitations: Mice lack a cone-dense fovea, so macular sparing in patients cannot be modelled.
    evidence:
    - reference: PMID:36115851
      reference_title: Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Over time, a gradual reduction of PNA signal was observed, revealing a loss of the outer segments of cones at PM9 and a complete loss of the cones at PM12
      explanation: Histology of delayed cone loss.
- name: Shetland sheepdog with CNGA1 frameshift (progressive retinal atrophy)
  species: Dog
  genotype: CNGA1 c.1752_1755delAACT (frameshift, exon 9)
  publication: PMID:26202106
  description: >-
    Naturally occurring progressive retinal atrophy in one Shetland sheepdog family associated with a CNGA1 frameshift. Its retinal phenotype has not been characterized in detail, and other affected Shelties in the population did not carry the variant.
  evidence:
  - reference: PMID:26202106
    reference_title: Progressive retinal atrophy in Shetland sheepdog is associated with a mutation in the CNGA1 gene.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Sequencing of this gene identified a 4-bp deletion in exon 9 (c.1752_1755delAACT), leading to a frameshift and a premature stop codon.
    explanation: Identifies the canine CNGA1 allele associated with progressive retinal atrophy.
experimental_models:
- name: Patient-derived iPSC line SJTUGHi002-A (CNGA1 c.265delC homozygous)
  experimental_model_type: CELL_LINE
  description: >-
    Induced pluripotent stem cell line reprogrammed from blood cells of a 36-year-old man with retinitis pigmentosa homozygous for the recurrent c.265delC frameshift. It is a resource for differentiating patient retinal cells; no retinal phenotype has yet been reported from it, so it is not linked to a mechanism node.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:38340451
  evidence:
  - reference: PMID:38340451
    reference_title: Establishment of the induced pluripotent stem cell line SJTUGHi002-A from a CNGA1-related recessive retinitis pigmentosa patient.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we established the human induced pluripotent stem cell line (iPSC) SJTUGHi002-A, generated from peripheral blood mononuclear cells of a 36-year-old male RP patient, who carried a homozygous frameshift variant in CNGA1 gene (c.265delC; p.L89Ffs*4)
    explanation: Describes the patient-derived line and its genotype.
- name: Patient-derived iPSC line BTHBIOi001-A (CNGA1 p.R420Q homozygous)
  experimental_model_type: CELL_LINE
  description: >-
    Induced pluripotent stem cell line from a woman with retinitis pigmentosa homozygous for the CNGA1 missense variant c.1621G>A (p.R420Q). Characterized for pluripotency only; no retinal phenotype has been reported.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:40795580
  evidence:
  - reference: PMID:40795580
    reference_title: Generation of a human iPSC line (BTHBIOi001-A) from a retinitis pigmentosa patient with CNGA1 gene mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a human iPSC line of a retinitis pigmentosa patient was generated, with the mutation of CNGA1 gene (homozygous c.1621G > A; p.R 420 > Q)
    explanation: Describes the patient-derived line and its genotype.
treatments:
- name: AAV-Mediated CNGA1 Gene Augmentation Therapy
  therapeutic_modality: GENE_THERAPY
  description: >-
    Investigational. Subretinal AAV8-hRHO-mCnga1 restores rod function, reverses cGMP accumulation and preserves photoreceptors in the Cnga1 knockout mouse. An intravitreal AAV2.NN-CNGA1 vector (VG901) is in a phase 1b open-label safety study in patients. Human efficacy has not been established.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Loss of Rod Light Responses
    treatment_effect: RESTORES
    description: Restores rod-mediated retinal function in the knockout mouse when given before major rod loss.
    evidence:
    - reference: PMID:40897815
      reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Gene augmentation therapy results in robust expression of correctly localized CNGA1 protein, sustained rescue of retinal function and long-term preservation of photoreceptors for at least 9 months.
      explanation: Preclinical restoration of rod function and structure.
  - target: Rod cGMP Accumulation
    treatment_effect: INHIBITS
    description: Reverses abnormal cGMP accumulation in treated retina.
    evidence:
    - reference: PMID:40897815
      reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We found that this toxic accumulation was reversed in the treated retina, whereas cGMP levels remained high in untreated eyes
      explanation: Immunohistochemical reversal of cGMP accumulation.
  evidence:
  - reference: PMID:40897815
    reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: To the best of our knowledge, this work demonstrates for the first time that a gene augmentation approach can restore vision and preserves photoreceptors in an animal model of CNGA1-RP.
    explanation: Preclinical proof of concept for CNGA1 gene augmentation.
  - reference: clinicaltrials:NCT06291935
    reference_title: A Prospective, Open-label, Phase 1b, Single-arm, Safety Study of an Intravitreal Application of a Recombinant Adeno-associated Virus Vector Expressing CNGA1 (AAV2.NN-CNGA1) in Patients With Retinitis Pigmentosa Due to CNGA1 Mutations
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Participants will be administered a single intravitreal dose of VG901 into the most affected eye through a syringe and followed up for a year to monitor safety and efficacy.
    explanation: Registered first-in-human study design; it reports no results.
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: OCT imaging demonstrated long-term preservation of the foveal ellipsoid zone until stage 4, indicating a broad therapeutic window.
    explanation: Preserved foveal photoreceptors in stages 1 to 3 define a population that could be treated; this is natural-history data, not treatment efficacy.
- name: Genetic counseling
  therapeutic_modality: OTHER
  description: >-
    Counseling explains autosomal recessive recurrence, carrier testing of relatives once the familial CNGA1 variants are known, and eligibility for gene-specific trials.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: At conception, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    explanation: General autosomal recessive retinitis pigmentosa recurrence risk, applicable to CNGA1 families.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Carrier testing for at-risk relatives requires prior identification of the RP- related pathogenic variants in the family.
    explanation: Carrier testing depends on knowing the familial variants.
- name: Low-vision rehabilitation
  therapeutic_modality: OTHER
  description: Low-vision aids and mobility, vocational and independent-living support address visual disability. This is general retinitis pigmentosa supportive care and does not restore channel function.
  treatment_term:
    preferred_term: Low-vision rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields.
    explanation: General retinitis pigmentosa guidance supports functional aids.
- name: Carbonic anhydrase inhibition for cystoid macular edema
  therapeutic_modality: SMALL_MOLECULE
  description: Oral acetazolamide or topical dorzolamide may be used for retinitis pigmentosa-associated cystoid macular edema; response is variable and rebound can occur. This is complication-directed care without CNGA1-specific trial evidence.
  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
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Some therapeutic success has been reported with both systemic and topical carbonic anhydrase inhibitors ... however, rebound edema can occur with continued use
    explanation: General retinitis pigmentosa treatment synthesis.
- name: Cataract surgery when visually significant
  therapeutic_modality: SURGERY
  description: Cataract is common in middle age and impairs acuity; extraction is considered when it contributes materially to visual loss, recognizing a higher risk of postoperative inflammation and macular edema in retinitis pigmentosa.
  treatment_term:
    preferred_term: Cataract Surgery
    term:
      id: NCIT:C157809
      label: Cataract Surgery
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Surgical extraction had been performed in 21 patients at a mean age of 53.6 ± 11.0 years.
    explanation: Cataract extraction is common in CNGA1 patients.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Individuals with retinitis pigmentosa are at a greater-than-average risk for postoperative inflammation and induced CME.
    explanation: General retinitis pigmentosa perioperative consideration.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: NEUROLOGIC
diagnosis:
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    An inherited retinal disease panel or exome identifies biallelic CNGA1 variants. Missense variants of uncertain significance may need functional data or segregation; a whole-gene deletion has been reported, so copy-number assessment is relevant.
  results: Biallelic pathogenic or likely pathogenic CNGA1 variants in trans.
  evidence:
  - reference: PMID:25268133
    reference_title: Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Whole exome sequencing of 30 arRP/spRP patients identified disease-causing gene mutations of CNGA1 (four patients)
    explanation: Exome sequencing identifies CNGA1 disease among unsolved arRP patients.
  - reference: PMID:42192302
    reference_title: Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Data mining revealed 86 missense CNGA1 variants - including three novel - most of them lacking functional data; 65.1% of the variants were initially classified as VUS.
    explanation: Most CNGA1 missense variants are initially of uncertain significance, so interpretation needs functional support.
- name: Full-field electroretinography
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: Full-field ERG documents a rod-cone pattern; responses are nonrecordable in most adults.
  results: Severely reduced or nonrecordable scotopic responses, with relatively preserved but attenuated photopic responses in early disease.
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Scotopic responses in these patients were severely reduced or nonrecordable, whereas photopic responses were relatively preserved, although attenuated.
    explanation: Characteristic ERG pattern in CNGA1 patients with recordable responses.
- name: Multimodal retinal imaging and perimetry
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Ultra-widefield fundus autofluorescence can stage disease by the size and presence of the hyperautofluorescent ring; OCT tracks ellipsoid-zone width, epiretinal membrane and cystoid change; static perimetry was proposed as the most promising trial endpoint.
  results: Hyperautofluorescent ring constricting with stage; ellipsoid-zone width declining over years.
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The FAF-based staging system provides a reliable framework for severity assessment and reveals stage-specific progression patterns, with no significant genotype-phenotype association observed.
    explanation: Autofluorescence staging stratifies CNGA1 disease severity.
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Static perimetry appears to be the most promising primary endpoint for future clinical trials.
    explanation: Perimetry is the proposed outcome measure.
- name: Ophthalmic surveillance
  diagnosis_term:
    preferred_term: Eye Examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  description: General retinitis pigmentosa guidance recommends annual dilated examination and perimetry, with closer review for complications such as cystoid macular edema and cataract.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: and a full ophthalmoscopic examination with dilation are performed on an annual basis, with more frequent follow up for active complications such as cystoid macular edema.
    explanation: General retinitis pigmentosa surveillance guidance.
progression:
- phase: Childhood-onset night blindness
  age_range: Early childhood
  notes: Night blindness is the first symptom, with mean onset around 4 years in one cohort and childhood onset in 88% of another.
  evidence:
  - reference: PMID:42440411
    reference_title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Nyctalopia was the initial symptom in all patients (100%), with a mean age at onset of 4.4 ± 2.7 years.
    explanation: Establishes early-childhood onset.
- phase: Progressive visual field constriction with preserved central acuity
  age_range: Childhood to fourth decade
  notes: Field loss begins in childhood and reaches tunnel vision at a median of about 39 years, while acuity remains stable until about 30 years.
  evidence:
  - reference: PMID:41448483
    reference_title: Natural History of CNGA1-Associated Retinitis Pigmentosa in a Large Chinese Cohort Revealing an Optimal Intervention Window.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Based on the quantitative data, VA loss in CNGA1-RP is late-onset and slow-progressing, whereas VF loss occurs earlier and more severely.
    explanation: Field loss precedes acuity loss.
  - reference: PMID:38705136
    reference_title: Genotypic and Phenotypic Characterization of a Cohort of Patients Affected by Rod Cyclic Nucleotide Channel-Associated Retinitis Pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Rod CNG channel-associated RP was demonstrated to be a slowly progressive disease in both CNGA1- and CNGB1-related forms
    explanation: An Italian cohort including 11 CNGA1 patients also found slow progression.
- phase: Central visual decline and complications
  age_range: Fourth decade onward
  notes: Acuity declines slowly from the fourth decade, with cataract, epiretinal membrane and macular atrophy contributing; about a third were blind by age 72 in the Chinese cohort.
  evidence:
  - reference: PMID:41448483
    reference_title: Natural History of CNGA1-Associated Retinitis Pigmentosa in a Large Chinese Cohort Revealing an Optimal Intervention Window.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: BCVA remained stable (0.09 logMAR) until age of 30.7 years, followed by a progressive decline at 0.029 logMAR per year; by age of 72 years, 32% of patients had developed blindness (BCVA > 1.30 logMAR).
    explanation: Quantifies late acuity decline.
clinical_trials:
- name: NCT06291935
  phase: PHASE_I
  status: RECRUITING
  description: >-
    Phase 1b open-label, single-arm safety study of a single intravitreal dose of an AAV vector expressing CNGA1 (AAV2.NN-CNGA1, VG901) in patients with retinitis pigmentosa due to CNGA1 variants, with low- and high-dose cohorts followed for one year. Status as recorded on ClinicalTrials.gov in October 2026.
  evidence:
  - reference: clinicaltrials:NCT06291935
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The goal of this phase 1 clinical trial is to learn about the safety and efficacy of a gene therapy, VG901, in patients with a rare disorder of the eye called Retinitis Pigmentosa.
    explanation: Registry record of the first CNGA1 gene therapy trial.
references:
- reference: PMID:7479749
  title: Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.
- reference: PMID:11970862
  title: An intersubunit interaction regulates trafficking of rod cyclic nucleotide-gated channels and is disrupted in an inherited form of blindness.
- reference: PMID:15570217
  title: Autosomal recessive retinitis pigmentosa in a Pakistani family mapped to CNGA1 with identification of a novel mutation.
- reference: PMID:20301590
  title: Nonsyndromic Retinitis Pigmentosa Overview.
  tags:
  - GeneReviews
- reference: PMID:25268133
  title: Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.
- reference: PMID:26202106
  title: Progressive retinal atrophy in Shetland sheepdog is associated with a mutation in the CNGA1 gene.
- reference: PMID:26802146
  title: Novel compound heterozygous mutation in the CNGA1 gene underlie autosomal recessive retinitis pigmentosa in a Chinese family.
- reference: PMID:27391953
  title: Novel compound heterozygous mutations in CNGA1in a Chinese family affected with autosomal recessive retinitis pigmentosa by targeted sequencing.
- reference: PMID:30652268
  title: A Novel CNGA1 Gene Mutation (c.G622A) of Autosomal Recessive Retinitis Pigmentosa Leads to the CNGA1 Protein Reduction on Membrane.
- reference: PMID:34418172
  title: Retinal degeneration in mice lacking the cyclic nucleotide-gated channel subunit CNGA1.
- reference: PMID:34699778
  title: Structural mechanisms of assembly, permeation, gating, and pharmacology of native human rod CNG channel.
- reference: PMID:36115851
  title: Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.
- reference: PMID:37054604
  title: CNG channel-related retinitis pigmentosa.
- reference: PMID:38340451
  title: Establishment of the induced pluripotent stem cell line SJTUGHi002-A from a CNGA1-related recessive retinitis pigmentosa patient.
- reference: PMID:38705136
  title: Genotypic and Phenotypic Characterization of a Cohort of Patients Affected by Rod Cyclic Nucleotide Channel-Associated Retinitis Pigmentosa.
- reference: PMID:40897815
  title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
- reference: PMID:40795580
  title: Generation of a human iPSC line (BTHBIOi001-A) from a retinitis pigmentosa patient with CNGA1 gene mutation.
- reference: PMID:41448483
  title: Natural History of CNGA1-Associated Retinitis Pigmentosa in a Large Chinese Cohort Revealing an Optimal Intervention Window.
- reference: PMID:42192302
  title: Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.
- reference: PMID:42440411
  title: "Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials."
- reference: clinicaltrials:NCT06291935
  title: A Prospective, Open-label, Phase 1b, Single-arm, Safety Study of an Intravitreal Application of a Recombinant Adeno-associated Virus Vector Expressing CNGA1 (AAV2.NN-CNGA1) in Patients With Retinitis Pigmentosa Due to CNGA1 Mutations
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
  title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1417/pdf/Bookshelf_NBK1417.pdf
  tags:
  - GeneReviews
discussions:
- discussion_id: cnga1_cgmp_death_intermediates
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which intermediates link CNGA1 channel loss and cGMP accumulation to rod death?
  attaches_to:
  - pathophysiology#Rod cGMP Accumulation
  - pathophysiology#Progressive Rod Photoreceptor Degeneration
  rationale: >-
    In CNGA1-deficient mice, cGMP accumulates, microglia activate, oxidative damage appears and chaperone-mediated autophagy coincides with rod death, and gene augmentation reverses cGMP accumulation while preserving rods. None of these studies isolates which event is causal for death. A null channel removes the cGMP-gated calcium influx, so the route from cGMP accumulation to death may differ from degenerations in which the open channel overloads the rod with calcium.
  evidence:
  - reference: PMID:34418172
    reference_title: Retinal degeneration in mice lacking the cyclic nucleotide-gated channel subunit CNGA1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In addition, the down-regulated PI3K-AKT-mTOR pathway indicated upregulation of autophagic process, and chaperone-mediated autophagy was further shown to coincide with the time course of photoreceptor death.
    explanation: Temporal coincidence, not causation, between autophagy and photoreceptor death.
- discussion_id: cnga1_mouse_progression_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Why do Cnga1-deficient mice lose photoreceptors within months while patients keep central acuity for decades, and which model predicts response to treatment at a human-relevant stage?
  attaches_to:
  - animal_models#Cnga1 knockout mouse (CRISPR/Cas9)
  - treatments#AAV-Mediated CNGA1 Gene Augmentation Therapy
  rationale: >-
    The CRISPR knockout loses most photoreceptors by 6 months and was treated at postnatal day 14, before major rod loss, whereas the Y509C mouse degenerates more slowly for unknown reasons. Patients present after years of rod loss but with preserved foveal photoreceptors. Rescue after treatment at a later stage has not been tested in a CNGA1 model.
  evidence:
  - reference: PMID:40897815
    reference_title: Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In the current study, we treated Cnga1-/- mice at an early stage of the disease to assess the maximal potential of gene augmentation therapy; however, patients with RP are often diagnosed at a later stage of the disease.
    explanation: The authors identify the treatment-stage gap themselves.

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References & Deep Research

References

22

PMID:7479749

Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.