Identification and Functional Analysis of a Novel MIP Gene Mutation Associated with Congenital Cataract in a Chinese Family.
Identification and Functional Analysis of a Novel MIP Gene Mutation Associated with Congenital Cataract in a Chinese Family.
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中国家族中与先天性白内障相关的一个新的MIP基因突变的鉴定和功能分析
DOI：
10.1371/journal.pone.0126679
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Shentu X;Miao Q;Tang X;Yin H;Zhao Y
先天性白内障是儿童视力障碍和失明的主要原因，先前的研究表明约1/3的非综合征性先天性白内障是遗传的。透镜的主要内在蛋白（MIP），也称为水通道蛋白0（AQP 0），在透镜的透明度和发育中起关键作用。迄今为止，已有超过10种MIP突变与人类遗传性白内障有关。在这项研究中，我们调查了一个四代中国人患有先天性进行性皮质点状白内障的家族的遗传和功能缺陷。对候选基因的突变筛查发现MIP的448位（c.448G>C）错义突变，导致保守的天冬氨酸在密码子150处被组氨酸取代（p.D150H）。通过连锁分析和单倍型分析，我们在候选位点两侧的微卫星标记D12 S1632（Zmax = 1.804，α = 1.000）和D12 S1691（Zmax = 1.806，α = 1.000）获得了正的多点对数比值（LOD）得分。PolyPhen-2和SIFT的预测结果表明，p.D150H突变可能对AQP 0的结构和功能造成损伤。野生型和p.D150H突变型AQP 0分别在HeLa细胞中表达，免疫荧光结果显示WT-AQP 0分布于质膜和细胞质中，而AQP 0-D150 H不能到达质膜，主要滞留在高尔基体中。此外，AQP 0-D150 H的蛋白水平显着低于野生型AQP 0在膜富集的裂解液中，当HEK-293 T细胞分别转染相同数量的野生型和突变型质粒。综上所述，我们的数据表明p.D150H突变是MIP中的一种新的致病突变，其通过损害AQP 0的运输机制导致先天性进行性皮质点状白内障。
Congenital cataracts are major cause of visual impairment and blindness in children and previous studies have shown about 1/3 of non-syndromic congenital cataracts are inherited. Major intrinsic protein of the lens (MIP), also known as AQP0, plays a critical role in transparency and development of the lens. To date, more than 10 mutations in MIP have been linked to hereditary cataracts in humans. In this study, we investigated the genetic and functional defects underlying a four-generation Chinese family affected with congenital progressive cortical punctate cataract. Mutation screening of the candidate genes revealed a missense mutation at position 448 (c.448G>C) of MIP, which resulted in the substitution of a conserved aspartic acid with histidine at codon 150 (p.D150H). By linkage and haplotype analysis, we obtained positive multipoint logarithm of odds (LOD) scores at microsatellite markers D12S1632 (Zmax = 1.804 at α = 1.000) and D12S1691 (Zmax = 1.806 at α = 1.000), which flanked the candidate locus. The prediction results of PolyPhen-2 and SIFT indicated that the p.D150H mutation was likely to damage to the structure and function of AQP0. The wild type and p.D150H mutant AQP0 were expressed in HeLa cells separately and the immunofluorescence results showed that the WT-AQP0 distributed at the plasma membrane and in cytoplasm, while AQP0-D150H failed to reach the plasma membrane and was mainly retained in the Golgi apparatus. Moreover, protein levels of AQP0-D150H were significantly lower than those of wide type AQP0 in membrane-enriched lysates when the HEK-293T cells were transfected with the same amount of wild type and mutant plasmids individually. Taken together, our data suggest the p.D150H mutation is a novel disease-causing mutation in MIP, which leads to congenital progressive cortical punctate cataract by impairing the trafficking mechanism of AQP0.
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影响因子：
64.8
作者：
Gonen, T;Sliz, P;Walz, T
通讯作者：
Walz, T
DOI：
10.1073/pnas.0802401105
发表时间：
2008-09-23
影响因子：
11.1
作者：
Jensen, Morten O.;Dror, Ron O.;Shaw, David E.
通讯作者：
Shaw, David E.
影响因子：
3.4
作者：
Kalman, Katalin;Nemeth-Cahalan, Karin L.;Hall, James E.
通讯作者：
Hall, James E.
影响因子：
4
作者：
Liu, Bing-Fen;Liang, Jack J.
通讯作者：
Liang, Jack J.
影响因子：
3.4
作者：
Kumari, Sindhu S.;Gandhi, Jason;Mustehsan, Mohammed H.;Eren, Semih;Varadaraj, Kulandaiappan
通讯作者：
Varadaraj, Kulandaiappan