A novel GJA8 mutation (p.V44A) causing autosomal dominant congenital cataract.
A novel GJA8 mutation (p.V44A) causing autosomal dominant congenital cataract.
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DOI：
10.1371/journal.pone.0115406
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yao K
中科院分区：
文献类型：
--
作者：
Zhu Y;Yu H;Wang W;Gong X;Yao K
旨在研究中国家庭中一种新型连接蛋白 50 (Cx50) 突变 Cx50 V44A 导致缝合保留常染色体显性先天性核性白内障的机制。记录家族史和临床数据，并使用直接基因测序来识别致病突变。 Cx50 基因是从人类晶状体 cDNA 文库中克隆的。通过荧光显微镜评估连接蛋白的分布。通过染料摄取测定分析半通道功能。通过染料转移实验评估功能通道的形成。对候选 GJA8 基因的直接测序揭示了外显子 2 中新的 c.131T>C 转变，该转变与该家族中的疾病共分离，并导致 Cx50 蛋白胞外环 1 中密码子 44（p.V44A）处的缬氨酸残基被丙氨酸取代。如神经生物素转移测定所示，Cx50 和 Cx50V44A 均形成功能性间隙连接。然而，与野生型 Cx50 不同，Cx50V44A 在染料摄取实验中无法形成开放的半通道。这项工作在中国人群中发现了一种独特的先天性白内障，由新突变 Cx50V44A 引起，并表明 V44A 突变特异性损害半通道的门控，但不损害间隙连接通道。功能失调的半通道导致人类先天性白内障的发生。
To examine the mechanism by which a novel connexin 50 (Cx50) mutation, Cx50 V44A, in a Chinese family causes suture-sparing autosomal dominant congenital nuclear cataracts. Family history and clinical data were recorded and direct gene sequencing was used to identify the disease-causing mutation. The Cx50 gene was cloned from a human lens cDNA library. Connexin protein distributions were assessed by fluorescence microscopy. Hemichannel functions were analyzed by dye uptake assay. Formation of functional channels was assessed by dye transfer experiments. Direct sequencing of the candidate GJA8 gene revealed a novel c.131T>C transition in exon 2, which cosegregated with the disease in the family and resulted in the substitution of a valine residue with alanine at codon 44 (p. V44A) in the extracellular loop 1 of the Cx50 protein. Both Cx50 and Cx50V44A formed functional gap junctions, as shown by the neurobiotin transfer assay. However, unlike wild-type Cx50, Cx50V44A was unable to form open hemichannels in dye uptake experiments. This work identified a unique congenital cataract in the Chinese population, caused by the novel mutation Cx50V44A, and it showed that the V44A mutation specifically impairs the gating of the hemichannels but not the gap junction channels. The dysfunctional hemichannels resulted in the development of human congenital cataracts.
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影响因子：
4
作者：
Banks EA;Toloue MM;Shi Q;Zhou ZJ;Liu J;Nicholson BJ;Jiang JX
通讯作者：
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影响因子：
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影响因子：
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