Department of Ophthalmology and Visual Science, Eye & ENT Hospital, Shanghai Medical College of Fudan University, NHC Key Laboratory of Myopia, Fudan University, Shanghai Key Laboratory of Visual Impairment and Restoration, China.
Department of Ophthalmology and Visual Science, Eye & ENT Hospital, Shanghai Medical College of Fudan University, NHC Key Laboratory of Myopia, Fudan University, Shanghai Key Laboratory of Visual Impairment and Restoration, China.
Gene. 2019 Sep 10;713:143973. doi: 10.1016/j.gene.2019.143973. Epub 2019 Jul 10.
Eye development in vertebrates is a highly coordinated multistep process while defects in key factors might lead to severe congenital ocular disorders. SMO encodes a G protein-coupled receptor that functions in Hedgehog signal transduction, an essential step during eye development. Here we reported the first identification of compound heterozygous mutations (c.G338A; p.R113Q and c.C1619T; p.A540V) in the SMO gene in a patient with both anterior segment dysgenesis (congenital corneal opacity, cataract) and morning glory syndrome, using trio-based whole exome sequencing. The clinical manifestations of this patient were quite consistent with the phenotypes observed in murine SMO null mutants. In silico bioinformatics analyses showed that the newly identified mutations revealed extremely low allele frequencies in the general populations, and were predicted to affect SMO protein stability and residues physiochemical properties. Further investigations revealed a significant decrease of SMO expression in the patient compared with healthy controls (0.71 ± 0.04 vs. 1.49 ± 0.29, P = 0.0265). Therefore, this study pinpoints, for the first time, the potential key sites in SMO that contribute to the maintenance of healthy ocular development, highlighting potential targets for upcoming gene therapy.
脊椎动物的眼睛发育是一个高度协调的多步骤过程，而关键因素的缺陷可能导致严重的先天性眼部疾病。SMO 编码一种 G 蛋白偶联受体，在 Hedgehog 信号转导中发挥作用，这是眼睛发育过程中的一个重要步骤。在这里，我们报道了首例在一名同时患有眼前段发育不良（先天性角膜混浊、白内障）和朝露症候群的患者中，SMO 基因的复合杂合突变（c.G338A;p.R113Q 和 c.C1619T;p.A540V）的鉴定，使用基于 trio 的全外显子组测序。该患者的临床表现与鼠 SMO 缺失突变体观察到的表型非常一致。计算机生物信息学分析表明，新鉴定的突变在普通人群中的等位基因频率极低，预计会影响 SMO 蛋白的稳定性和残基的理化性质。进一步的研究表明，与健康对照组相比，患者的 SMO 表达显著下降（0.71±0.04 对 1.49±0.29，P=0.0265）。因此，这项研究首次确定了 SMO 中维持健康眼部发育的潜在关键位点，为即将到来的基因治疗提供了潜在的靶点。
