A novel missense mutation in the gene for gap-junction proteinα3 (GJA3) associated with autosomal dominant "nuclearpunctate" cataracts linked to chromosome 13q

[摘要] Purpose: Autosomal dominant cataracts are a clinically andgenetically heterogeneous eye-lens disorder that usually present inchildhood with symptoms of impaired vision. The purpose of this studywas to map and identify the mutation underlying autosomal dominantnuclear punctate cataracts segregating in a six generation Caucasianpedigree.Methods: Genomic DNA was prepared from blood leucocytes, genotypingwas performed using microsatellite markers, and LOD scores werecalculated using the LINKAGE programs. Mutation detection was performedusing direct sequencing and restriction fragment length analysis.Results: Significant evidence of linkage was obtained at markerD13S175 (LOD score [Z]=4.11, recombination fraction [θ]=0.0) andhaplotyping indicated that the disease gene lay in the about 2 Mbphysical interval between D13S1316 and D13S1236, which contained thegene for gap-junction protein α3 (GJA3) or connexin46.Sequencing of GJA3 detected a C->T transition in exon 2 thatresulted in the gain of an Alu 1 restriction site and was predictedto cause a conservative substitution of proline to leucine at codon 59(P59L). Restriction analysis confirmed that the novel Alu 1 siteco-segregated with cataracts in the family but was not detected in acontrol panel of 170 normal unrelated individuals.Conclusions: The present study has identified a fifth mutation inGJA3, rendering this connexin gene one of the most commonnon-crystallin genes associated with autosomal dominant cataracts inhumans.

[学科分类] 生物化学/生物物理