Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy
Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy
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DOI：
10.1038/ejhg.2014.136
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发表时间：
2015-04-01
影响因子：
5.2
通讯作者：
Ahmed, Zubair M.
中科院分区：
文献类型：
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作者：
Shaikh, Rehan S.;Reuter, Peggy;Ahmed, Zubair M.
我们评估了一个巴基斯坦大家庭（PKAB157），该家庭隔离了早发性低视力问题。对受影响个体的眼底镜和视网膜电图评估显示青少年锥杆营养不良（CRD）伴有黄斑病变。其他临床症状包括颜色辨别能力丧失、畏光和眼球震颤。全外显子组测序、分离和单倍型分析表明，CNGA3 中的过渡变体 (c.955T>C; p.(Cys319Arg)) 与 PKAB157 家族中的 CRD 表型共分离。当 CNGA3 通道单独表达或与 HEK293 细胞中的野生型 CNGB3 亚基一起表达时，CNGA3 通道响应激动剂而流入钙的能力由于 p 被完全消除。 Cys319Arg 变体。蛋白质印迹和免疫定位研究表明，由于 CNGA3 蛋白折叠和/或运输受损，HEK293 细胞膜通道密度降低是 p 的主要致病作用。 Cys319Arg 变体。人类视锥光感受器环核苷酸门控通道 (CNGA3) 的突变等位基因通常与色盲有关。在极少数情况下，CNGA3 的变异还与视锥细胞营养不良、莱伯氏先天性黑蒙和寡视锥细胞三色觉有关。 CNGA3 中预测的 p.(Cys319Arg) 错义变异的鉴定扩展了 CRD 的已知遗传原因和 CNGA3 等位基因的表型谱。
We assessed a large consanguineous Pakistani family (PKAB157) segregating early onset low vision problems. Funduscopic and electroretinographic evaluation of affected individuals revealed juvenile cone-rod dystrophy (CRD) with maculopathy. Other clinical symptoms included loss of color discrimination, photophobia and nystagmus. Whole-exome sequencing, segregation and haplotype analyses demonstrated that a transition variant (c.955T>C; p.(Cys319Arg)) in CNGA3 co-segregated with the CRD phenotype in family PKAB157. The ability of CNGA3 channel to influx calcium in response to agonist, when expressed either alone or together with the wild-type CNGB3 subunit in HEK293 cells, was completely abolished due to p. Cys319Arg variant. Western blotting and immunolocalization studies suggest that a decreased channel density in the HEK293 cell membrane due to impaired folding and/or trafficking of the CNGA3 protein is the main pathogenic effect of the p. Cys319Arg variant. Mutant alleles of the human cone photoreceptor cyclic nucleotide-gated channel (CNGA3) are frequently associated with achromatopsia. In rare cases, variants in CNGA3 are also associated with cone dystrophy, Leber's congenital amaurosis and oligo cone trichromacy. The identification of predicted p.(Cys319Arg) missense variant in CNGA3 expands the repertoire of the known genetic causes of CRD and phenotypic spectrum of CNGA3 alleles.