Molecular characterization of two large Canadian pedigrees with autosomal dominant optic atrophy.

Abstract

Abstract: : Purpose: Autosomal dominant optic atrophy (ADOA), or Kjer optic atrophy, is an acquired, hereditary condition demonstrating variable expressivity and almost complete penetrance. To date, one gene and one additional locus have been described for this condition: OPA1 maps to chromosome 3q28–29 and another locus (gene not yet identified) to chromosome 18q12.2–12.3. The purpose of this study was to examine, at the clinical and molecular level, two large Canadian pedigrees with ADOA to determine whether a phenotype–genotype association exists for this condition. Methods: Two Canadian pedigrees (I and II) were ascertained, and all consenting family members were examined clinically including psychophysical testing of affected individuals. Blood samples were obtained for DNA extraction. The DNA was tested for linkage using haplotype and linkage analysis. Mutation screening of OPA1 was performed using single–strand conformational polymorphism and DNA sequence analysis. Results: Pedigree I failed to demonstrate linkage to either known locus, and mutation screening of OPA1, including sequencing, was negative. The second pedigree of Danish origin mapped to the OPA1 locus, and a mutation (2826delT) was detected, causing a frameshift in exon 28. The mutation segregated completely with the disease and was identical to that identified previously in other large pedigrees from Denmark. The range of phenotype differed between Pedigrees I and II. Pedigree I demonstrated greater visual perception deficits and Pedigree II showed more retinal involvement. Conclusions: The results suggest that a phenotype–genotype association exists for ADOA. Also, Pedigree I failed to map to either of the known loci for ADOA, suggesting the presence of a third locus for this condition.

Keywords: gene/expression • neuro–ophthalmology: optic nerve • gene screening