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The PDE6C gene encodes the catalytic α′ subunit of cone photoreceptor phosphodiesterase vital for cGMP hydrolysis in cone phototransduction. Pathogenic variants in PDE6C cause autosomal recessive cone dystrophy, characterized by reduced visual acuity, poor color discrimination, photophobia, central scotoma, and macular atrophy. Onset is typically in childhood with early cone dysfunction on electroretinography and progressive central vision loss. Disease inheritance is autosomal recessive with both homozygous and compound heterozygous loss-of-function or missense variants. This summary synthesizes clinical, genetic, and experimental evidence supporting the PDE6C–cone dystrophy association.
In an Iranian consanguineous family, three affected siblings with congenital cone dystrophy harbored a novel homozygous nonsense variant c.1644G>A (p.Trp548Ter) segregating with disease (3 probands; [PMID:38956522]). All showed decreased visual acuity, photophobia, central scotoma, and macular atrophy with normal anterior segment findings. Segregation confirmed autosomal recessive transmission of the PDE6C variant in cis with a PDZD7 allele but independently segregating for cone dystrophy.
In a large Saudi family, three individuals homozygous for the splice-site variant c.481-1G>A in PDE6C developed cone dystrophy, whereas family members homozygous for only the AIRE variant had APS1 without retinal involvement (3 probands; [PMID:37433860]). This dual molecular diagnosis underscores the independent recessive inheritance of PDE6C-related cone dystrophy in consanguineous pedigrees.
A cohort of four patients (two pediatric, two adult) exhibited cone or cone-rod dystrophy with PDE6C variants identified by next-generation sequencing ([PMID:33001157]). Clinical presentation included decreased acuity, poor color vision, constricted fields, and night blindness in cone-rod cases. Structural imaging showed minimal changes in children versus clear macular dystrophy in adults, highlighting phenotypic variability.
The variant spectrum comprises at least 11 distinct alleles: nonsense (e.g., c.1644G>A (p.Trp548Ter)), splice-site (c.481-1G>A), missense (e.g., c.967T>A (p.Tyr323Asn), c.2368G>A (p.Glu790Lys)), and frameshift changes. No recurrent or founder variants have been reported beyond isolated consanguineous cohorts. Carrier frequency remains low in population databases.
Functional assays demonstrate that four of six missense PDE6C mutants exhibit baseline catalytic inactivity, indicating functional null alleles, while p.Glu790Lys and p.Tyr323Asn reduce activity by ~60–80% ([PMID:21127010]). Expression of mutant PDE6C in Xenopus rods revealed altered proteolytic stability and mislocalization for regulatory‐domain variants (e.g., p.Met455Val, p.Arg104Trp; [PMID:25461672]). These data confirm loss-of-function as the primary pathological mechanism.
Together, genetic and experimental concordance across independent families and model systems provides strong evidence for an autosomal recessive PDE6C–cone dystrophy link. Additional studies have not refuted this association. Key take-home: PDE6C loss-of-function variants should be prioritized in genetic testing for early-onset cone dystrophy due to their diagnostic and prognostic significance.
Gene–Disease AssociationStrong10 unrelated probands from four families with co-segregation and concordant functional data Genetic EvidenceStrong10 probands with AR inheritance, compound heterozygous and homozygous LoF/missense variants in four families ([PMID:38956522], [PMID:37433860], [PMID:33001157]) Functional EvidenceModerateBiochemical assays demonstrating loss of catalytic activity for PDE6C missense mutants and in vivo models showing disrupted proteolytic stability and localization ([PMID:21127010], [PMID:25461672]) |