PDE6A – Retinitis Pigmentosa

PDE6A encodes the rod photoreceptor cGMP-specific phosphodiesterase alpha subunit and is causally linked to autosomal recessive retinitis pigmentosa (Retinitis Pigmentosa) through loss-of-function and missense variants that disrupt phototransduction. Biallelic variants in PDE6A lead to progressive rod-cone dystrophy characterized by nyctalopia, constricted visual fields, and eventual central vision loss (HP:0000510). Genetic testing for PDE6A is therefore integral to molecular diagnosis and patient stratification for emerging therapies.

Genetic evidence for PDE6A in RP is strong. The initial report screened 340 unrelated RP probands and identified biallelic PDE6A variants segregating with disease in two families, each altering essential catalytic domains (PMID:7493036). Subsequent case series described homozygous and compound heterozygous variants in over 57 patients from 44 families, including recurrent alleles such as c.304C>A (p.Arg102Ser) and novel frameshifts like c.1358_1359delAT (p.Ile452SerfsTer7) (PMID:29118501; PMID:33057649). Parental carrier status and familial segregation have been demonstrated in multiple pedigrees, confirming recessive inheritance.

The variant spectrum in PDE6A is broad, comprising over 50 distinct loss-of-function changes (nonsense, canonical splice, frameshift), >15 missense substitutions, and several intronic splice-site mutations. Key recurrent alleles include c.84C>G (p.Tyr28Ter) and c.304C>A (p.Arg102Ser), observed across diverse populations. Novel founder variants have been reported in Middle Eastern and East Asian cohorts, reflecting ethnic-specific allele frequencies.

Experimental studies support haploinsufficiency and catalytic deficiency as pathogenic mechanisms. Mouse models carrying Pde6a V685M and R562W alleles recapitulate human photoreceptor degeneration, showing elevated cGMP, calpain activation, and non-apoptotic cell death (PMID:26188004). Induced pluripotent stem cell lines from patients exhibit impaired photoreceptor differentiation and loss of PDE6A expression, consistent with in vivo findings.

No credible reports dispute the PDE6A–RP association. The consistency of segregation, phenotype concordance, and functional concordance across species strengthens clinical validity.

In summary, PDE6A meets Definitive ClinGen criteria for autosomal recessive retinitis pigmentosa, with strong genetic and moderate experimental evidence. Genetic testing for PDE6A variants enables accurate diagnosis, genetic counseling, and identification of candidates for gene supplementation trials.

References

• Nature Genetics • 1995 • Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase PMID:7493036
• Oman journal of ophthalmology • 2017 • Novel PDE6A mutation in an Emirati patient with retinitis pigmentosa PMID:29118501
• JAMA ophthalmology • 2020 • Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial PMID:33057649
• Human Molecular Genetics • 2015 • Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype PMID:26188004

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