A Novel Cx50 Insert Mutation from a Chinese Congenital Cataract Family Impairs Its Cellular Membrane Localization and Function
A Novel Cx50 Insert Mutation from a Chinese Congenital Cataract Family Impairs Its Cellular Membrane Localization and Function
复制标题
来自中国先天性白内障家族的新型 Cx50 插入突变损害其细胞膜定位和功能。
DOI：
10.1089/dna.2017.4051
复制
发表时间：
2018-02-28
影响因子：
3.1
通讯作者：
Hu, Yanzhong
中科院分区：
文献类型：
--
作者：
Cui, Xiukun;Zhou, Zheng;Hu, Yanzhong
GJA 8的突变与遗传性常染色体显性和隐性白内障的形成有关。本研究在一个中国先天性白内障家系中发现了一个新的GJA 8插入突变，并与该家系的疾病共分离。该插入突变在Cx 50蛋白的第二跨膜（TM 2）结构域内的95位点（p.H95_A96insYAVHY）处的组氨酸之后引入了5个额外的氨基酸残基YAVHY（Cx 50-插入物）。与野生型Cx 50蛋白相比，Cx 50插入蛋白的异位表达损害人透镜上皮细胞中的半通道功能和间隙连接活性。Cx 50插入蛋白从细胞质膜错配到内质网和溶酶体。在小鼠透镜组织中，我们的研究结果表明，Cx 50主要表达于透镜过渡带的上皮细胞和纤维细胞，提示其在透镜分化中的作用。综上所述，这些数据表明，在Cx 50蛋白的TM 2结构域的新的插入突变，这损害了其运输到细胞膜和间隙连接功能，与白内障的形成在这个中国家系。
Mutations in GJA8 are associated with hereditary autosomal dominant and recessive cataract formation. In this study, a novel insert mutation in GJA8 was identified in a Chinese congenital cataract family and cosegregated with the disease in this pedigree. This insert mutation introduces five additional amino acid residues YAVHY after histidine at the 95 site (p.H95_A96insYAVHY) within the second transmembrane (TM2) domain of Cx50 protein (Cx50-insert). Ectopic expression of Cx50-insert protein impairs the hemichannel functions and gap junction activity compared to wild-type Cx50 protein in human lens epithelial cells. Cx50-insert proteins were mislocated from cytoplasmic membrane to endoplasmic reticulum and lysosome. In mouse lens tissue, our results showed that Cx50 predominant expresses in epithelial cells and fiber cells at the transition zone of lens hinting its roles in lens differentiation. Taken together, these data suggest that the novel insert mutation in the TM2 domain of Cx50 protein, which impairs its trafficking to the cell membrane and gap-junction function, is associated with the cataract formation in this Chinese pedigree.