An aberrant sequence in a Connexin46 mutant underlies congenital cataracts
An aberrant sequence in a Connexin46 mutant underlies congenital cataracts
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DOI：
10.1074/jbc.m504765200
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发表时间：
2005-12-09
影响因子：
4.8
通讯作者：
Berthoud, VM
中科院分区：
文献类型：
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作者：
Minogue, PJ;Liu, XQ;Berthoud, VM
越来越多的疾病已被定位到编码离子通道蛋白的基因，包括差距连接蛋白，连接蛋白。在这里，我们报告的一个氨基酸序列的识别相关的非功能性突变连接蛋白46（CX 46）与先天性白内障的行为。突变蛋白CX 46 fs 380比CX 46长31个氨基酸，在其C末端含有87个异常氨基酸。当在哺乳动物细胞中表达时，未发现突变体CX 46存在于间隙连接斑，但其与ERGIC和高尔基体标记物显示出广泛的共定位。通过产生含有CX 46突变体异常C末端的最后三分之一（或更多）的嵌合体，将间隙连接斑的功能和形成的严重降低转移到其他连接蛋白。该序列也损害了CD 8嵌合体的运输。定点突变的二苯丙氨酸恢复并置膜定位和功能。这些结果表明了一种新的机制，其中突变通过产生导致在合成/分泌途径内保留的基序而引起疾病。
An increasing number of diseases have been mapped to genes coding for ion channel proteins, including the gap junction proteins, connexins. Here, we report on the identification of an amino acid sequence underlying the behavior of a non-functional mutant connexin46 (CX46) associated with congenital cataracts. The mutant protein, CX46fs380, is 31 amino acids longer than CX46 and contains 87 aberrant amino acids in its C terminus. When expressed in mammalian cells, the mutant CX46 was not found at gap junctional plaques, but it showed extensive co-localization with markers for ERGIC and Golgi. The severe reductions in function and formation of gap junctional plaques were transferred to other connexins by creating chimeras containing the last third ( or more) of the aberrant C terminus of the CX46 mutant. This sequence also impaired trafficking of a CD8 chimera. Site-directed mutagenesis of a diphenylalanine restored appositional membrane localization and function. These results suggest a novel mechanism in which a mutation causes disease by generating a motif that leads to retention within the synthetic/secretory pathway.