DOMINANT OPTIC ATROPHY - EXCLUSION AND FINE GENETIC-MAPPING OF THE CANDIDATE GENE, HRY

Autosomal dominant optic atrophy (OPA1) maps to Chromosome (Chr) 3q28, and the disease interval has been refined to within 1.4 cM, flanked b y the markers D3S3669 and D3S3562. HRY, the human homolog of the Droso phila segmentation gene, hairy, maps by in situ hybridization to the c hromosomal region 3q28-q29. We screened for mutations in HRY in 36 pat ients from 18 pedigrees with dominant optic atrophy and a group of nor mal control individuals. Heteroduplex mutation analysis and direct seq uencing of all four coding exons and one upstream putative untranslate d exon were performed. No disease-associated sequence alterations were identified. A polymorphism in the untranslated region of exon 2 was f ound, with four alleles. PCR amplification of this part of exon 2 in f our of the pedigrees affected by autosomal dominant optic atrophy mapp ing to chromosome 3q, followed by haplotype analysis, showed recombina tion between HRY and OPA1 in one pedigree. This allows us to genetical ly position HRY in relation to known microsatellite markers in the reg ion, placing HRY telomeric to marker D3S3562 and centromeric to D3S130 5. This is outside the published critical disease interval for dominan t optic atrophy. We have, therefore, excluded HRY as the gene for domi nant optic atrophy by sequence analysis, mapped it genetically, and id entified a polymorphism in our population.