title: A novel GJA8 mutation (p.V44A) causing autosomal dominant congenital cataract.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Eye center, 2nd Affiliated Hospital of Medical College, Zhejiang University, Hangzhou, China; Key Laboratory of Ophthalmology of Zhejiang Province, Wenzhou, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Neurobiology, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.affiliation: Eye center, 2nd Affiliated Hospital of Medical College, Zhejiang University, Hangzhou, China; Key Laboratory of Ophthalmology of Zhejiang Province, Wenzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Optometry and Vision Science Program, University of California, Berkeley, California, United States of America.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Gong
authors.affiliation: Eye center, 2nd Affiliated Hospital of Medical College, Zhejiang University, Hangzhou, China; Key Laboratory of Ophthalmology of Zhejiang Province, Wenzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yao
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D002386:Cataract / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D002648:Child; D017630:Connexins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D055815:Young Adult; D000099264:Connexin 50
chemical_list: D017630:Connexins; D000099264:Connexin 50