Whole-Exome Sequencing Identifies Mutations in GPR179 Leading to Autosomal-Recessive Complete Congenital Stationary Night Blindness
Whole-Exome Sequencing Identifies Mutations in GPR179 Leading to Autosomal-Recessive Complete Congenital Stationary Night Blindness
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DOI：
10.1016/j.ajhg.2011.12.007
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发表时间：
2012-02-10
影响因子：
9.8
通讯作者：
Zeitz, Christina
中科院分区：
文献类型：
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作者：
Audo, Isabelle;Bujakowska, Kinga;Zeitz, Christina
先天性静止性夜盲（CSNB）是一种异质性视网膜疾病，其特征是在低光照条件下出现视力障碍。这种疾病是由于视网膜中视杆光感受器向相邻双极细胞的信号传递缺陷所致。临床上可区分出两种类型，完全性CSNB（cCSNB）和不完全性CSNB；这两种类型是根据受影响的信号通路来区分的。在外丛状层（OPL）表达的NYX、GRM6和TRPM1基因的突变会导致ON - 双极细胞反应中断，并且在cCSNB患者中已被发现。对已知基因无突变的cCSNB患者进行全外显子组测序，在一个近亲常染色体隐性遗传的cCSNB家族中鉴定出一个纯合错义突变（c.1807C>T [p.His603Tyr]），在一名单发男性cCSNB患者中鉴定出GPR179基因的一个纯合移码突变（c.278delC [p.Pro93Glnfs*57]）。对40名患者进行的桑格测序进一步筛查，又发现了另外3名cCSNB患者在GPR179基因中存在其他等位基因突变。尽管免疫组织学研究显示野生型小鼠视网膜的外网状层（OM）中有Gpr179，但Gpr179并不与特定的ON - 双极标记物共定位。有趣的是，Gpr179高度集中在水平细胞和米勒细胞终足中。这些细胞在cCSNB中的作用以及GPR179的具体功能仍有待阐明。
Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (Oft) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1.807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs*57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OM in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Muller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated.