in autosomal dominant optic atrophy linked to chromosome 3q28

Autosomal dominant optic atrophy (ADOA) is the most preva- lent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atro- phy of the optic nerve with an onset within the first two decades of life1,2. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin- related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alter- ations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably rep- resent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mito- chondrial membrane integrity. ADOA occurs with an estimated disease prevalence of between 1:12,000 (refs 4,5) and 1:50,000 (ref. 6). The disease is highly vari- able in expression and shows incomplete penetrance in some fami- lies 1,2,7 . Histopathological post-mortem examination of donor eyes suggests that the fundamental