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Abstract：
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.
摘要：
锥形光感受器功能障碍代表一组临床异质性疾病，特征为眼球震颤，畏光,中央或彩色视觉降低，和黄斑营养不良.这里,我们描述了色盲的分子发现和临床表现，部分或完全没有色觉，在三个近亲的巴基斯坦家庭中，与三个已知的CNGA3错义变体共同分离。眼底检查和光学相干断层扫描（OCT）成像显示近视，薄视网膜，视网膜色素上皮细胞在中央凹/中央凹丢失，和黄斑萎缩.Sanger和整个外显子组测序的组合揭示了三个已知的纯合错义变体（c.827A>G，p.(Asn276Ser)；c.847C>T，p.(Arg283Trp)；c.1279C>T，p。（Arg427Cys））在CNGA3中，即视锥感光细胞中环核苷酸门控阳离子通道的α亚基。预测所有三种变体都会取代进化保守的氨基酸，并通过特定的硅片程序致病，与在异源细胞中观察到的CNGA3的膜靶向改变一致。我们研究的见解将有助于有关CNGA3相关视锥营养不良的分子和表型景观的咨询。
