GUCA1A – Cone Dystrophy

Guanylate cyclase-activating protein 1 (GCAP1), encoded by GUCA1A, is a neuronal calcium sensor that regulates retinal guanylate cyclase (RetGC1) in photoreceptors. Heterozygous missense variants in GUCA1A cause autosomal dominant cone dystrophy, presenting with early color vision defects and reduced visual acuity due to dysregulated cGMP homeostasis in cones ([PMID:9651312]).

Genetic evidence spans over 10 unrelated pedigrees ([PMID:9651312]) with at least 10 distinct pathogenic missense variants such as c.296A>G (p.Tyr99Cys) and c.464A>G (p.Glu155Gly) segregating with disease ([PMID:11146732]). Variants cluster in EF-hand domains 2–4, and recurrent alleles (Tyr99Cys, Pro50Leu, Glu155Gly, Leu84Phe, Leu151Phe) have been reported in multiple families.

Segregation analyses report 19 affected relatives co-segregating with GUCA1A variants ([PMID:11146732]). The clinical spectrum includes isolated cone dystrophy and progressive cone-rod dystrophy depending on the mutation and family context.

Functional assays demonstrate that the Tyr99Cys mutation causes constitutive RetGC1 activation at physiological and elevated Ca2+ levels ([PMID:9651312]). Other variants (E155G, L151F) similarly impair Ca2+ inhibition and maintain elevated cyclase activity, consistent with a gain-of-function mechanism ([PMID:11484154], [PMID:15790869]).

Transgenic mouse models expressing GCAP1(L151F) recapitulate photoreceptor degeneration, and RNAi-mediated knockdown of mutant GCAP1 rescues retinal structure and function, supporting targetability of GUCA1A-related disease ([PMID:23472098]).

Variable expressivity is noted for Pro50Leu, which ranges from mild macular involvement to full cone-rod dystrophy within the same family ([PMID:11146732]).

Overall, GUCA1A–cone dystrophy has a Definitive ClinGen classification with Strong genetic and Moderate functional evidence supporting an AD gain-of-function etiology. Key Take-home: GUCA1A mutation screening is essential for accurate diagnosis and paves the way for allele-specific therapies.

References

• The Journal of biological chemistry • 1998 • Constitutive activation of photoreceptor guanylate cyclase by Y99C mutant of GCAP-1. Possible role in causing human autosomal dominant cone degeneration. PMID:9651312
• Archives of ophthalmology • 2001 • Autosomal dominant cone and cone-rod dystrophy with mutations in the guanylate cyclase activator 1A gene-encoding guanylate cyclase activating protein-1. PMID:11146732
• American journal of human genetics • 2001 • Identification and functional consequences of a new mutation (E155G) in the gene for GCAP1 that causes autosomal dominant cone dystrophy. PMID:11484154
• Investigative ophthalmology & visual science • 2005 • A novel GCAP1 missense mutation (L151F) in a large family with autosomal dominant cone-rod dystrophy (adCORD). PMID:15790869
• PloS one • 2013 • RNAi-mediated gene suppression in a GCAP1(L151F) cone-rod dystrophy mouse model. PMID:23472098
• BioMed research international • 2013 • Novel GUCA1A mutations suggesting possible mechanisms of pathogenesis in cone, cone-rod, and macular dystrophy patients. PMID:24024198

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