GUCA1A – Cone-Rod Dystrophy

GUCA1A encodes guanylate cyclase-activating protein 1, a neuronal Ca²⁺ sensor critical for photoreceptor cGMP homeostasis. Heterozygous missense variants in GUCA1A cause autosomal dominant cone-rod dystrophy ([PMID:24352742]). Patients present with early central vision loss, progressive macular atrophy (HP:0007401), and characteristic electroretinogram findings showing greater cone than rod dysfunction.

Multiple independent family studies have identified pathogenic GUCA1A variants in over 40 unrelated AD-CORD probands across more than 10 kindreds. A novel p.Asp100Gly (c.299A>G (p.Asp100Gly)) variant segregates with disease in three affected members of a single pedigree ([PMID:24352742]), while Japanese, French, Spanish, and broader cohorts report additional segregating variants in EF-hand domains ([PMID:31728034], [PMID:28442884], [PMID:30184081]). Segregation is supported by co-inheritance in at least 9 affected relatives.

The variant spectrum comprises primarily EF-hand missense changes (e.g., p.Asp100Gly, p.Tyr99Cys, p.Leu151Phe, p.Glu111Val) and in-frame deletions (e.g., p.Val101del). Recurrent hotspots around EF-hand 3 and 4 (residues 99–102, 148–155) suggest critical Ca²⁺-binding perturbed sites. Population studies find GUCA1A variants in ~1.2% of Chinese CORD probands and ~0.25% of Japanese IRD families, indicating a low but definitive prevalence.

Biochemical and biophysical assays demonstrate that pathogenic variants disrupt Ca²⁺-binding affinity, leading to constitutive activation of retinal guanylate cyclase even at inhibitory Ca²⁺ levels. In vitro expression of GCAP1 variants (e.g., Y99C, p.Pro50Leu, p.L151F) shows altered Ca²⁺ sensitivity and thermal stability ([PMID:9651312], [PMID:15790869]). Transgenic and knockout mouse models recapitulate photoreceptor degeneration, and RNAi-mediated knockdown of mutant GCAP1 rescues retinal structure and function ([PMID:23472098]).

Some GUCA1A variants (e.g., p.L80I, p.Y99S) do not co-segregate with disease and are classified as benign. Functional discordance in non-pathogenic variants underscores the importance of thorough biochemical validation and pedigree analysis to avoid misclassification.

Together, robust segregation in multiple AD families, extensive functional modeling, and successful rescue experiments fulfill ClinGen criteria for a definitive association between GUCA1A and autosomal dominant cone-rod dystrophy. Key take-home: GUCA1A variant testing informs early diagnosis and potential RNAi-based therapeutic strategies.

References

• Documenta ophthalmologica. Advances in ophthalmology • 2014 • Disease progression in autosomal dominant cone-rod dystrophy caused by a novel mutation (D100G) in the GUCA1A gene. PMID:24352742
• Scientific reports • 2019 • Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies. PMID:31728034
• Human molecular genetics • 2018 • A novel p.(Glu111Val) missense mutation in GUCA1A associated with cone-rod dystrophy leads to impaired calcium sensing and perturbed second messenger homeostasis in photoreceptors. PMID:30184081
• 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
• 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

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