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In an autosomal dominant maculopathy, heterozygous variants in GUCA1A have been linked to central areolar choroidal dystrophy (MONDO:0008982). A five-generation family exhibited variable maculopathies, ranging from mild photoreceptor degeneration to central areolar choroidal dystrophy, in which the novel c.359_360delinsTT (p.Arg120Leu) variant segregated with disease across ≥8 affected individuals, supported by linkage analysis and whole-exome sequencing (PMID:28125083).
The inheritance mode is autosomal dominant with full penetrance in adulthood. Aside from p.Arg120Leu, another variant, c.298G>C (p.Asp100His), previously implicated in cone dystrophy, was examined in the same model system but is not recurrent in central areolar choroidal dystrophy.
Zebrafish expressing human p.Arg120Leu showed significant disruption of photoreceptors and retinal pigment epithelium (RPE), with secondary atrophy of retinal vessels and the choriocapillaris. Exogenous wild-type GUCA1A failed to fully rescue these defects, indicating a gain-of-function effect of p.Arg120Leu. The p.Asp100His variant similarly impaired RPE and photoreceptor integrity, consistent with a dominant-negative mechanism (PMID:28125083).
GUCA1A encodes guanylate cyclase-activating protein 1 (GCAP1), a Ca²⁺ sensor that regulates photoreceptor guanylate cyclase activity during light adaptation. Gain-of-function mutations likely disrupt Ca²⁺ homeostasis by constitutively activating cyclase, leading to cGMP overproduction and photoreceptor degeneration.
No studies to date have refuted this association or identified alternative modes of inheritance for GUCA1A in central areolar choroidal dystrophy.
Key Take-home: Heterozygous GUCA1A gain-of-function variants, notably c.359_360delinsTT (p.Arg120Leu), cause autosomal dominant central areolar choroidal dystrophy through aberrant Ca²⁺-mediated cyclase activation, supporting their use in genetic diagnosis and guiding therapeutic development.
Gene–Disease AssociationModerateOne five-generation family (≥8 affected) segregating GUCA1A c.359_360delinsTT (p.Arg120Leu) with linkage and concordant functional data Genetic EvidenceModerateAutosomal dominant segregation of c.359_360delinsTT across 5 generations in a well-characterized pedigree (PMID:28125083) Functional EvidenceModerateZebrafish models of p.Arg120Leu and p.Asp100His display photoreceptor and RPE disruption with partial rescue, indicating gain-of-function mechanism (PMID:28125083) |