Whole-Exome Sequencing Identifies LRIT3 Mutations as a Cause of Autosomal-Recessive Complete Congenital Stationary Night Blindness
Whole-Exome Sequencing Identifies LRIT3 Mutations as a Cause of Autosomal-Recessive Complete Congenital Stationary Night Blindness
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DOI：
10.1016/j.ajhg.2012.10.023
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发表时间：
2013-01-10
影响因子：
9.8
通讯作者：
Audo, Isabelle
中科院分区：
文献类型：
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作者：
Zeitz, Christina;Jacobson, Samuel G.;Audo, Isabelle
先天性静止性夜盲（CSNB）是一种临床和遗传异质性视网膜疾病。临床上可以区分两种形式：完全CSNB（cCSNB）和不完全CSNB。患有cCSNB的个体在低光条件下有视觉障碍，并显示特征性视网膜电图（ERG）。在ERG的暗适应状态下，b波振幅严重降低，表示ON双极细胞功能异常。此外，患有cCSNB的个体可以显示其他眼部特征，例如眼球震颤、近视和斜视，并且可以具有降低的视敏度和视锥ERG波形的异常。这种形式的遗传方式可以是X连锁或常染色体隐性遗传，迄今为止已经描述了四个基因（NYX，GRM 6，TRPM 1和GPR 179）的功能障碍。在一个缺乏已知基因突变的单纯性cCSNB病例中进行全外显子组测序，鉴定出LRIT 3中的错义突变（c.983G>A [p.Cys328Tyr]）和无义突变（c.1318C>T [p.Arg440*]），编码富含亮氨酸重复序列（LRR）、免疫球蛋白样和跨膜结构域3（LRIT 3）。随后对89例CSNB患者进行桑格测序，发现另一例cCSNB病例在同一基因中存在一个无义突变（c.1151 C>G [p.Ser384*]）和一个预计会导致提前终止密码子的缺失（c.1538_1539 del [p.Ser513 Cysfs *59]）。人LRIT 3抗体染色揭示了在人视网膜的外丛状层中类似于双极细胞的树突状尖端的点状标记模式;已经观察到与cCSNB有关的其他蛋白质的类似模式。这种LRR蛋白在cCSNB中的确切作用仍有待阐明。
Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disorder. Two forms can be distinguished clinically: complete CSNB (cCSNB) and incomplete CSNB. Individuals with cCSNB have visual impairment under low-light conditions and show a characteristic electroretinogram (ERG). The b-wave amplitude is severely reduced in the dark-adapted state of the ERG, representing abnormal function of ON bipolar cells. Furthermore, individuals with cCSNB can show other ocular features such as nystagmus, myopia, and strabismus and can have reduced visual acuity and abnormalities of the cone ERG waveform. The mode of inheritance of this form can be X-linked or autosomal recessive, and the dysfunction of four genes (NYX, GRM6, TRPM1, and GPR179) has been described so far. Whole-exome sequencing in one simplex cCSNB case lacking mutations in the known genes led to the identification of a missense mutation (c.983G>A [p.Cys328Tyr]) and a nonsense mutation (c.1318C>T [p.Arg440*]) in LRIT3, encoding leucine-rich-repeat (LRR), immunoglobulin-like, and transmembrane-domain 3 (LRIT3). Subsequent Sanger sequencing of 89 individuals with CSNB identified another cCSNB case harboring a nonsense mutation (c.1151C>G [p.Ser384*]) and a deletion predicted to lead to a premature stop codon (c.1538_1539del [p.Ser513Cysfs*59]) in the same gene. Human LRIT3 antibody staining revealed in the outer plexiform layer of the human retina a punctate-labeling pattern resembling the dendritic tips of bipolar cells; similar patterns have been observed for other proteins implicated in cCSNB. The exact role of this LRR protein in cCSNB remains to be elucidated.