A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect

Dominant optic atrophy (DOA) is a hereditary optic neuropathy characterised by decreased visual acuity, colour vision deficits, centro-coecal scotoma and optic nerve pallor. The gene OPA1, encoding a dynamin-related GTPase, h as recently been identified within the genetic linkage interval for the maj or locus for DOA on chromosome 3q28 and shown to harbour genetic aberration s segregating with disease in DOA families. The prevalence of the disorder in Denmark is reported to be the highest of any geographical location, sugg estive of a founder effect. In order to establish the genetic basis of dise ase in a sample of 33 apparently unrelated Danish families. we screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. A novel identical mutation in exon 28 (2826delT) was as sociated with DOA in 14 pedigrees and led to a frameshift and abnormal OPA1 protein -COOH terminus. Haplotype analysis of a region of similar to1 Mb f lanking the OPA1 gene using eight polymorphic markers revealed a common hap lotype shared by all 14 patients, this haplotype was markedly over-represen ted compared with ethnically matched controls. Statistical analysis confirm ed significant linkage disequilibrium with DOA over similar to 600 kb encom passing the disease mutation. We have therefore demonstrated that the relat ively high frequency of DOA in Denmark is attributable to a founder mutatio n responsible for similar to 42% of the examined families and suggest that presymptomatic screening for the (2826delT) mutation may facilitate diagnos is and genetic counselling in a significant proportion of DOA patients of D anish ancestry.