A novel GJA8 mutation is associated with autosomal dominant lamellar pulverulent cataract:: further evidence for gap junction dysfunction in human cataract -: art. no. e2
A novel GJA8 mutation is associated with autosomal dominant lamellar pulverulent cataract:: further evidence for gap junction dysfunction in human cataract -: art. no. e2
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DOI：
10.1136/jmg.2005.034108
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发表时间：
2006-01-01
影响因子：
4
通讯作者：
Berthoud, VM
中科院分区：
文献类型：
--
作者：
Arora, A;Minogue, PJ;Berthoud, VM
目的：目的：确定一个四代英国人常染色体显性遗传性板层粉状白内障家系的致病基因，并分析该突变对白内障功能和细胞的影响。直接测序GJA8基因。结果：在连接蛋白50（Cx50）编码区存在一个262 C> A的突变，导致脯氨酸被谷氨酰胺（P88 Q）取代。hCx50 P88 Q不诱导细胞间传导，并显着抑制缝隙连接活性的共表达野生型hCx50 RNA在配对的非洲爪蟾卵母细胞。在转染的细胞中，免疫反应hCx50P88Q被限制在细胞质中，但表现出温度敏感的本地化在间隙连接plaques.Conclusions：在这个家庭中描述的粉状白内障与一种新的GJA8突变，并具有不同的临床表型从以前描述的GJA8突变体。白内障可能是由于缺乏间隙连接功能。功能的缺乏与质膜靶向不当有关，最可能是由于蛋白质错误折叠。
Purpose: To identify the gene responsible for autosomal dominant lamellar pulverulent cataract in a four-generation British family and characterise the functional and cellular consequences of the mutation.Methods: Linkage analysis was used to identify the disease locus. The GJA8 gene was sequenced directly. Functional behaviour and cellular trafficking of connexins were examined by expression in Xenopus oocytes and HeLa cells.Results: A 262C > A transition that resulted in the replacement of proline by glutamine (P88Q) in the coding region of connexin50 (Cx50) was identified. hCx50P88Q did not induce intercellular conductance and significantly inhibited gap junctional activity of co-expressed wild type hCx50 RNA in paired Xenopus oocytes. In transfected cells, immunoreactive hCx50P88Q was confined to the cytoplasm but showed a temperature sensitive localisation at gap junctional plaques.Conclusions: The pulverulent cataract described in this family is associated with a novel GJA8 mutation and has a different clinical phenotype from previously described GJA8 mutants. The cataract likely results from lack of gap junction function. The lack of function was associated with improper targeting to the plasma membrane, most probably due to protein misfolding.