title: A novel missense mutation in the gene for gap-junction protein alpha3 (GJA3) associated with autosomal dominant "nuclear punctate" cataracts linked to chromosome 13q.
abstract: OBJECTIVE
  Autosomal dominant cataracts are a clinically and genetically heterogeneous eye-lens disorder that usually present in childhood with symptoms of impaired vision. The purpose of this study was to map and identify the mutation underlying autosomal dominant nuclear punctate cataracts segregating in a six generation Caucasian pedigree.
  
  
  METHODS
  Genomic DNA was prepared from blood leucocytes, genotyping was performed using microsatellite markers, and LOD scores were calculated using the LINKAGE programs. Mutation detection was performed using direct sequencing and restriction fragment length analysis.
  
  
  RESULTS
  Significant evidence of linkage was obtained at marker D13S175 (LOD score [Z]=4.11, recombination fraction [theta]=0.0) and haplotyping indicated that the disease gene lay in the about 2 Mb physical interval between D13S1316 and D13S1236, which contained the gene for gap-junction protein a3 (GJA3) or connexin46. Sequencing of GJA3 detected a C->T transition in exon 2 that resulted in the gain of an Alu 1 restriction site and was predicted to cause a conservative substitution of proline to leucine at codon 59 (P59L). Restriction analysis confirmed that the novel Alu 1 site co-segregated with cataracts in the family but was not detected in a control panel of 170 normal unrelated individuals.
  
  
  CONCLUSIONS
  The present study has identified a fifth mutation in GJA3, rendering this connexin gene one of the most common non-crystallin genes associated with autosomal dominant cataracts in humans.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bennett
authors.forename: Donna S
authors.initials: DS
authors.lastname: Mackay
authors.forename: Harry L S
authors.initials: HL
authors.lastname: Knopf
authors.forename: Alan
authors.initials: A
authors.lastname: Shiels
mesh_terms: D000293:Adolescent; D002386:Cataract / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D017630:Connexins; C082917:GJA3 protein, human