Abstract
GUCA1A gene variants are associated with autosomal dominant (AD) cone dystrophy (COD) and cone-rod dystrophy (CORD). GUCA1A-associated AD-COD/CORD has never been reported in the Japanese population. The purpose of this study was to investigate clinical and genetic features of GUCA1A-associated AD-COD/CORD from a large Japanese cohort. We identified 8 variants [c.C50_80del (p.E17VfsX22), c.T124A (p.F42I), c.C204G (p.D68E), c.C238A (p.L80I), c.T295A (p.Y99N), c.A296C (p.Y99S), c.C451T (p.L151F), and c.A551G (p.Q184R)] in 14 families from our whole exome sequencing database composed of 1385 patients with inherited retinal diseases (IRDs) from 1192 families. Three variants (p.Y99N, p.Y99S, and p.L151F), which are located on/around EF-hand domains 3 and 4, were confirmed as “pathogenic”, whereas the other five variants, which did not co-segregate with IRDs, were considered “non-pathogenic”. Ophthalmic findings of 9 patients from 3 families with the pathogenic variants showed central visual impairment from early to middle-age onset and progressive macular atrophy. Electroretinography revealed severely decreased or non-recordable cone responses, whereas rod responses were highly variable, ranging from nearly normal to non-recordable. Our results indicate that the three pathogenic variants, two of which were novel, underlie AD-COD/CORD with progressive retinal atrophy, and the prevalence (0.25%, 3/1192 families) of GUCA1A-associated IRDs may be low among Japanese patients.
Highlights
We identified eight rare guanylate cyclase activator 1A (GUCA1A) variants [c.C50_80del (p.E17VfsX22), c.T124A (p.F42I), c.C204G (p.D68E), c.C238A (p.L80I), c.T295A (p.Y99N), c.A296C (p.Y99S), c.C451T (p.L151F), and c.A551G (p.Q184R)] from 14 unrelated families after filtering (Supplementary Table S1)
We demonstrated clinical features of nine cone dystrophy (COD)/cone-rod dystrophy (CORD) patients from three unrelated Japanese families with two novel variants (p.Y99S and p.Y99N) and one known variant (p.L151F)
19 GUCA1A missense and 3 in-frame deletion/insertion variants in heterozygous states have been reported as causes of autosomal dominant (AD)-macular dystrophy (MD) and AD-COD/CORD in HGMD Professional (2019.3)[14,15,16,17,18,20,23,24,25,26,27,28,29,30,31,32,33]
Summary
In the dark-adapted state, when cytosolic Ca2+ concentration is high, GCAP-1 binds Ca2+ and inhibits RetGC activity and cGMP synthesis. Mutated GCAP-1 (e.g. p.Y99C, p.D100E, p.L151F) associated with disease-causing GUCA1A variants show persistently stimulated RetGC activity, leading to the elevation of cytosolic Ca2+ and cGMP concentrations and resulting in initiation of photoreceptor cell death[9,10,11,12,13]. We identified rare GUCA1A variants from our whole exome sequencing (WES) database composed of IRD patients from a large Japanese cohort. The purpose of this study was to investigate the pathogenicity of rare GUCA1A variants and clinical and genetic features of GUCA1A-associated IRDs
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