Functional impairment of lens aquaporin in two families with dominantly inherited cataracts
Functional impairment of lens aquaporin in two families with dominantly inherited cataracts
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DOI：
10.1093/oxfordjournals.hmg.a018925
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发表时间：
2000-09-22
影响因子：
3.5
通讯作者：
Agre, P
中科院分区：
文献类型：
--
作者：
Francis, P;Chung, JJ;Agre, P
眼晶状体混浊在普通人群中出现频率较高。临床表现不同的显性遗传性白内障发生在两个携带晶状体水通道蛋白AQPO(主要内在蛋白，MIP)基因不同点突变的家系中，E134G家系为单板层白内障，出生后稳定，而T138R家系为多灶性浑浊，并随年龄增加而增加。为了建立白内障形成的病理生理相关性，利用非洲爪哇卵母细胞表达系统对突变蛋白E134G和T138R的功能缺陷进行了评估。这两种替换都会导致膜水通道活性的丧失，这是因为突变蛋白向卵母细胞质膜的运输受到了损害。虽然AQP1和AQP2蛋白的错义突变在体内和体外都会导致隐性性状，但当E134G或T138R与野生型AQPO蛋白共表达时，突变蛋白表现出显性负行为。据我们所知，这些研究是第一次在体外证明患有先天性白内障的人类的AQPO蛋白具有功能缺陷。此外，这些观察预测，AQPO蛋白中不太严重的缺陷可能会导致常见的、不太剧烈的白内障患者的晶状体混浊。
Opacities in the crystalline lens of eye appear with high frequency in the general population. Dominantly inherited cataracts with differing clinical features were found in two families carrying different point mutations in the gene encoding lens water channel protein AQPO (major intrinsic protein, MIP), Families with E134G have a uni-lamellar cataract which is stable after birth, whereas families with T138R have multi-focal opacities which increase throughout life. To establish pathophysiological relevance of cataract formation, the Xenopus laevis oocyte expression system was employed to evaluate functional defects in the mutant proteins, E134G and T138R. Both substitutions cause loss of membrane water channel activity due to impaired trafficking of the mutant proteins to the oocyte plasma membrane. Although missense mutations in AQP1 and AQP2 proteins are known to result in recessive traits in vivo and in vitro, when E134G or T138R are co-expressed with wild-type AQPO protein, the mutant proteins exhibit dominant negative behaviour. To our knowledge, these studies represent the first in vitro demonstration of functionally defective AQPO protein from humans with congenital cataracts. Moreover, these observations predict that less severe defects in the AQPO protein may contribute to lens opacity in patients with common, less fulminant forms of cataracts.