OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance

We and others have shown recently that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein cause autosomal dominant optic atro phy (ADOA) linked to chromosome 3q28-q29. Here we report screening of the O PA1 gene in a sample of 78 independent ADOA families. OPA1 mutations were i dentified in 25 patients (detection rate 32.1%) including 16 novel mutation s. We successfully amplified OPA1 cDNA prepared from leukocyte RNA of three patients, and found the amount of transcripts harboring the Arg366Stop mut ation was significantly reduced compared with transcripts derived from the normal chromosome. Analysis of the distribution of OPA1 mutations in ADOA r evealed that most missense mutations cluster within the putative GTPase dom ain, and that there is a preponderance of mutations, which result in premat ure translation termination. These observations support the notion that hap loinsufficiency may represent a major pathomechanism for ADOA. In addition, we identified an ADOA patient who is a compound heterozygote for two OPA1 missense mutations. The fact that this patient is by far more severely affe cted than her simple heterozygotic parents and siblings implies that at lea st these OPA1 alleles behave semi-dominantly rather than purely dominantly. Clinical examination revealed considerable variability in disease expressi on among patients carrying OPA1 mutations and no strict correlation with ei ther the position or the type of mutation.