GUCA1B – Retinitis Pigmentosa

Guanylate cyclase-activating protein 2 (GCAP2; GUCA1B) has been implicated in autosomal dominant retinitis pigmentosa (RP) following targeted screening in Japanese RP cohorts. In 63 ADRP and 33 ARRP unrelated patients, a novel heterozygous transitional mutation c.469G>A (p.Gly157Arg) was identified in three independent families (three probands) demonstrating variable expressivity between RP and macular involvement (PMID:15452722).

Wild-type GCAP2 regulates phototransduction via high-affinity Ca2+ binding and modulates photoreceptor guanylyl cyclase (RetGC) activity independent of N-terminal myristoylation, establishing a baseline for comparison with disease variants (PMID:9162068).

Segregation analysis across the three families showed the c.469G>A (p.Gly157Arg) variant in six clinically affected members (five with RP, one with macular degeneration) and one asymptomatic carrier, consistent with incomplete penetrance (PMID:15452722).

Cellular studies demonstrate that the bovine-equivalent G157R substitution enhances GCAP2 phosphorylation and causes retention at the inner segment in rod photoreceptors, implicating disrupted trafficking in pathogenesis (PMID:29440717).

Biochemical characterization of the human GCAP2 G157R variant revealed a molten globule-like conformation, reduced cation-binding affinity and a propensity to aggregate, likely driving dominant-negative or toxic gain-of-function effects (PMID:33812995).

Together, the genetic findings and concordant functional data support a pathogenic role of GUCA1B c.469G>A (p.Gly157Arg) in autosomal dominant RP with variable expressivity and incomplete penetrance. Key take-home: GUCA1B c.469G>A (p.Gly157Arg) is a clinically actionable variant for genetic diagnosis and counseling in RP.

References

• Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie • 2005 • Mutations in the gene coding for guanylate cyclase-activating protein 2 (GUCA1B gene) in patients with autosomal dominant retinal dystrophies. PMID:15452722
• The Journal of Biological Chemistry • 1997 • Calcium binding, but not a calcium-myristoyl switch, controls the ability of guanylyl cyclase-activating protein GCAP-2 to regulate photoreceptor guanylyl cyclase. PMID:9162068
• Scientific Reports • 2018 • Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina. PMID:29440717
• The Journal of Biological Chemistry • 2021 • Molecular properties of human guanylate cyclase-activating protein 2 (GCAP2) and its retinal dystrophy-associated variant G157R. PMID:33812995

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