Arora A et al. (2006), A novel GJA8 mutation is associated with autoso...

XB-ART-875

J Med Genet 2006 Jan 01;431:e2. doi: 10.1136/jmg.2005.034108.

Show Gene links Show Anatomy links

A novel GJA8 mutation is associated with autosomal dominant lamellar pulverulent cataract: further evidence for gap junction dysfunction in human cataract.

Arora A , Minogue PJ , Liu X , Reddy MA , Ainsworth JR , Bhattacharya SS , Webster AR , Hunt DM , Ebihara L , Moore AT , Beyer EC , Berthoud VM .

???displayArticle.abstract???
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.

???displayArticle.pubmedLink??? 16397066
???displayArticle.pmcLink??? PMC2564510
???displayArticle.link??? J Med Genet
???displayArticle.grants??? [+]

Species referenced: Xenopus
Genes referenced: gja8
GO keywords: gap junction channel activity

???displayArticle.disOnts??? cataract 1 multiple types
???displayArticle.omims??? CATARACT 1, MULTIPLE TYPES; CTRCT1
References [+] :

Bennett, A novel missense mutation in the gene for gap-junction protein alpha3 (GJA3) associated with autosomal dominant "nuclear punctate" cataracts linked to chromosome 13q. 2004, Pubmed

Bennett, A novel missense mutation in the gene for gap-junction protein alpha3 (GJA3) associated with autosomal dominant "nuclear punctate" cataracts linked to chromosome 13q. 2004, Pubmed
Berry, Connexin 50 mutation in a family with congenital "zonular nuclear" pulverulent cataract of Pakistani origin. 1999, Pubmed
Berthoud, Loss of function and impaired degradation of a cataract-associated mutant connexin50. 2003, Pubmed
Burdon, A novel mutation in the Connexin 46 gene causes autosomal dominant congenital cataract with incomplete penetrance. 2004, Pubmed
Chang, A Gja8 (Cx50) point mutation causes an alteration of alpha 3 connexin (Cx46) in semi-dominant cataracts of Lop10 mice. 2002, Pubmed
Denning, Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. 1992, Pubmed , Xenbase
Ebihara, Distinct behavior of connexin56 and connexin46 gap junctional channels can be predicted from the behavior of their hemi-gap-junctional channels. 1995, Pubmed , Xenbase
Gerido, Genetic background influences cataractogenesis, but not lens growth deficiency, in Cx50-knockout mice. 2003, Pubmed
Gilbert, Causes of childhood blindness: results from west Africa, south India and Chile. 1993, Pubmed
Gong, Disruption of alpha3 connexin gene leads to proteolysis and cataractogenesis in mice. 1997, Pubmed
Gong, Genetic factors influence cataract formation in alpha 3 connexin knockout mice. 1999, Pubmed
Goodenough, Lens gap junctions: a structural hypothesis for nonregulated low-resistance intercellular pathways. 1979, Pubmed
Graw, Congenital hereditary cataracts. 2004, Pubmed
Jiang, A novel mutation in GJA3 (connexin46) for autosomal dominant congenital nuclear pulverulent cataract. 2003, Pubmed
Krutovskikh, Connexin gene mutations in human genetic diseases. 2000, Pubmed
Li, A novel connexin46 (GJA3) mutation in autosomal dominant congenital nuclear pulverulent cataract. 2004, Pubmed
Mackay, Connexin46 mutations in autosomal dominant congenital cataract. 1999, Pubmed
Pal, Molecular mechanism underlying a Cx50-linked congenital cataract. 1999, Pubmed , Xenbase
Polyakov, Mutation in the connexin 50 gene (GJA8) in a Russian family with zonular pulverulent cataract. 2001, Pubmed
Reddy, Molecular genetic basis of inherited cataract and associated phenotypes. 2004, Pubmed
Rees, Further evidence of autosomal dominant congenital zonular pulverulent cataracts linked to 13q11 (CZP3) and a novel mutation in connexin 46 (GJA3). 2000, Pubmed
Resnikoff, Global data on visual impairment in the year 2002. 2004, Pubmed
Ri, The role of a conserved proline residue in mediating conformational changes associated with voltage gating of Cx32 gap junctions. 1999, Pubmed , Xenbase
Saez, Plasma membrane channels formed by connexins: their regulation and functions. 2003, Pubmed
Shiels, A missense mutation in the human connexin50 gene (GJA8) underlies autosomal dominant "zonular pulverulent" cataract, on chromosome 1q. 1998, Pubmed
Steele, A mutation in the connexin 50 (Cx50) gene is a candidate for the No2 mouse cataract. 1998, Pubmed
Suchyna, Identification of a proline residue as a transduction element involved in voltage gating of gap junctions. 1993, Pubmed , Xenbase
Tong, Exchange of gating properties between rat cx46 and chicken cx45.6. 2004, Pubmed , Xenbase
White, Targeted ablation of connexin50 in mice results in microphthalmia and zonular pulverulent cataracts. 1998, Pubmed
Willoughby, A novel GJA8 mutation in an Iranian family with progressive autosomal dominant congenital nuclear cataract. 2003, Pubmed
Zheng, [A heterozygous transversion of connexin 50 in a family with congenital nuclear cataract in the northeast of China]. 2005, Pubmed