Delineating the Molecular and Phenotypic Spectrum of the CNGA3-Related Cone Photoreceptor Disorder in Pakistani Families.
Delineating the Molecular and Phenotypic Spectrum of the CNGA3-Related Cone Photoreceptor Disorder in Pakistani Families.
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描述巴基斯坦家庭中cnga3相关锥体光感受器障碍的分子和表型谱。
作者：
视锥细胞光感受器功能障碍是一组临床异质性疾病，其特征为眼球震颤、畏光、中心视力或色觉减退以及黄斑营养不良。在此，我们描述了全色盲（一种部分或完全丧失色觉的病症）的分子发现和临床表现，在三个巴基斯坦近亲结婚的大家系中，全色盲与CNGA3基因的三个已知错义变异共分离。眼底检查和光学相干断层扫描（OCT）成像显示存在近视、视网膜变薄、中央凹/中央凹周围视网膜色素上皮细胞缺失以及黄斑萎缩。桑格测序和全外显子组测序相结合，揭示了CNGA3基因（视锥细胞光感受器细胞中环核苷酸门控阳离子通道的α亚基）存在三个已知的纯合错义变异（c.827A>G，p.(Asn276Ser)；c.847C>T，p.(Arg283Trp)；c.1279C>T，p.(Arg427Cys)）。所有这三个变异预计会替换进化上保守的氨基酸，并且特定的计算机模拟程序预测其具有致病性，这与在异源细胞中观察到的CNGA3膜定位改变相一致。我们的研究成果将有助于就CNGA3相关视锥细胞营养不良的分子和表型情况提供遗传咨询。
Cone photoreceptor dysfunction represents a clinically heterogenous group of disorders characterized by nystagmus, photophobia, reduced central or color vision, and macular dystrophy. Here, we described the molecular findings and clinical manifestations of achromatopsia, a partial or total absence of color vision, co-segregating with three known missense variants of CNGA3 in three large consanguineous Pakistani families. Fundus examination and optical coherence tomography (OCT) imaging revealed myopia, thin retina, retinal pigment epithelial cells loss at fovea/perifovea, and macular atrophy. Combination of Sanger and whole exome sequencing revealed three known homozygous missense variants (c.827A>G, p.(Asn276Ser); c.847C>T, p.(Arg283Trp); c.1279C>T, p.(Arg427Cys)) in CNGA3, the α-subunit of the cyclic nucleotide-gated cation channel in cone photoreceptor cells. All three variants are predicted to replace evolutionary conserved amino acids, and to be pathogenic by specific in silico programs, consistent with the observed altered membrane targeting of CNGA3 in heterologous cells. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of CNGA3-related cone dystrophies.
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