CNGA1 – Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive photoreceptor degeneration, night blindness, and reduced visual acuity. Multiple independent case reports and multi‐patient studies have implicated CNGA1, which encodes the alpha subunit of the rod cyclic nucleotide‐gated channel, in autosomal recessive RP (PMID:26802146). The repeated identification of pathogenic variants in CNGA1 across diverse populations supports its role in the pathogenesis of this vision‐threatening condition.

Genetic investigations have revealed both compound heterozygous and homozygous variants in CNGA1 that segregate with disease in affected families. Notably, the variant c.1525G>A (p.Gly509Arg) has been documented in several studies, with more than 20 probands reported (PMID:26802146) and extended segregation among affected relatives (PMID:35573004). Such cumulative genetic evidence substantiates a strong gene‐disease association based on multiple independent observations and rigorous co‐segregation analyses.

Segregation studies further bolster the association, with affected family members frequently demonstrating the same CNGA1 variants and phenotypic features of RP. This concordance with autosomal recessive inheritance provides compelling support for the pathogenicity of these variants. In several families, the presence of deleterious mutations correlates strongly with the RP phenotype, affirming their diagnostic relevance (PMID:36115851).

Functional assessments have shown that mutant CNGA1 proteins exhibit altered cellular localization and impaired channel function, leading to deficient phototransduction and subsequent retinal degeneration. Both in vitro assays and animal models, including induced pluripotent stem cell studies, have recapitulated the RP phenotype seen in patients. These experimental data, while moderate in quantitative strength, are in concordance with the genetic findings and underscore a mechanistic basis for disease pathogenesis (PMID:38340451).

Integrating the genetic and functional evidence, CNGA1 emerges as a robust contributor to autosomal recessive retinitis pigmentosa. Although some studies report concurrent mutations in other retinal disease genes, the specific contribution of CNGA1 variants remains clear. The evidence spans multiple independent cohorts, with consistent segregation and experimental validation, exceeding the thresholds typically applied by ClinGen for a strong association.

Key take‐home: CNGA1 is a critical genetic marker for autosomal recessive RP, supporting accurate diagnosis and guiding the development of targeted therapeutic strategies.

References

• Bioscience reports • 2016 • Novel compound heterozygous mutation in the CNGA1 gene underlie autosomal recessive retinitis pigmentosa in a Chinese family PMID:26802146
• Cell death discovery • 2022 • Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model PMID:36115851
• Stem cell research • 2024 • Establishment of the induced pluripotent stem cell line SJTUGHi002-A from a CNGA1-related recessive retinitis pigmentosa patient PMID:38340451

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