A novel mutation in the connexin 46 gene (GJA3) causes autosomal dominant zonular pulverulent cataract in a Hispanic family.

PURPOSE: A five-generation Hispanic pedigree with autosomal dominant zonular pulverulent cataract was studied to identify the causative mutation in connexin 46 (Cx46), a gap junction protein responsible for maintaining lens homeostasis. METHODS: Twenty-six individuals from the family were comprehensively clinically examined. DNA was extracted from their peripheral blood samples. The DNA was used for automated genotyping with fluorescently labeled microsatellite markers and for mutation detection by automated sequencing. RESULTS: A novel D3Y missense mutation in GJA3 segregated with autosomal dominant (AD) zonular pulverulent cataract throughout the family. The mutation was absent in the unaffected individuals in the family and in 230 control chromosomes. CONCLUSIONS: A novel mutation causing AD zonular pulverulent cataract has been identified in a Hispanic Central American family. This is the first report of a mutation in GJA3 causing autosomal dominant congenital cataract (ADCC) in this ethnic group. It is also the first reported cataract-causing mutation in the NH2-terminal region of the Cx46 protein.

Posterior polar cataract is the predominant consequence of a recurrent mutation in the PITX3 gene.

BACKGROUND: The authors recently identified three large genetically unrelated families with an identical 17 base pair duplication mutation in exon 4 of the PITX3 gene. Here, they report the detailed clinical phenotype. METHODS: Affected and unaffected individuals in the three families with autosomal dominant posterior polar cataract underwent full clinical examination and donated blood samples for DNA extraction and molecular genetic studies. RESULTS: In all three families, an identical 17 base pair duplication mutation in PITX3 was identified which co-segregated with disease status in the family. All affected individuals had bilateral progressive posterior polar cataracts. In one family, posterior polar cataract was the only clinical abnormality but in the other two families, one of 10 affected individuals and four of 11 affected individuals also had anterior segment mesenchymal dysgenesis (ASMD). CONCLUSION: Mutations in the PITX3 gene in humans result in posterior polar cataract and variable ASMD. The gene encodes a transcription factor which has a key role in lens and anterior segment development. The mechanism by which the mutant protein gives rise to such a regional pattern of lens opacity remains to be elucidated.