Dominant cataract formation in association with a vimentin assembly disrupting mutation
Dominant cataract formation in association with a vimentin assembly disrupting mutation
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DOI：
10.1093/hmg/ddn440
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发表时间：
2009-03-15
影响因子：
3.5
通讯作者：
Magin, Thomas M.
中科院分区：
文献类型：
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作者：
Mueller, Martin;Bhattacharya, Shomi S.;Magin, Thomas M.
白内障的特征是晶状体混浊，通常由蛋白质错误折叠和聚集引起。在晶状体纤维细胞和间充质组织中高度表达的中间丝蛋白vimentin是这些细胞形成膜连接细胞骨架的主要结构决定因素。vimentin的其他功能仍有待确定。在这里，我们证明了VIM突变导致显性粉状白内障。我们对90例先天性白内障患者的VIM基因进行了全序列测序，发现单个患者的1外显子G596A发生变化，导致viimentin线圈1B中的E151K错义突变。突变体波形蛋白在转染细胞中形成异常的波形蛋白细胞骨架，并增加蛋白酶体活性。此外，这种突变在体内和体外都会导致严重的血凝蛋白组装动力学缺陷。因此，结合现有的小鼠和细胞培养模型，我们的研究结果首次揭示了vimentin在维持晶状体完整性中的重要功能作用。最后，这引发了新的白内障治疗方法。
Cataracts are characterized by an opacification of the eye lens, often caused by protein misfolding and aggregation. The intermediate filament protein vimentin, which is highly expressed in lens fiber cells and in mesenchymal tissues, is a main structural determinant in these cells forming a membrane-connected cytoskeleton. Additional functions of vimentin remain to be identified. Here, we demonstrate that a mutation in VIM causes a dominant, pulverulent cataract. We sequenced the complete human VIM gene in 90 individuals suffering from congenital cataract and found a G596A change in exon 1 in a single individual, causing the missense mutation E151K in coil 1B of vimentin. The mutant vimentin formed an aberrant vimentin cytoskeleton and increased the proteasome activity in transfected cells. Furthermore, this mutation causes a severe kinetic defect in vimentin assembly both in vitro and in vivo. Hence, in conjunction with available mouse and cell culture models, our results reveal for the first time an important functional role for vimentin in the maintenance of lens integrity. Finally, this invites novel therapy approaches for cataracts.