OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28

Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary op tic neuropathy resulting in progressive loss of visual acuity. centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset wi thin the first two decades of life(1,2). The predominant locus for this dis order (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. Th e gene comprises 28 coding exons and spans more than 40 kb of genomic seque nce. Upon sequence analysis. we identified mutations in seven independent f amilies with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these fa milies. Because most mutations probably represent null alleles, dominant in heritance of the disease may result from haploinsufficiency of OPA1. OPA1 i s widely expressed and is most abundant in the retina. The presence of cons ensus signal peptide sequences suggests that the product of the gene OPA1 i s targeted to mitochondria and may exert its function in mitochondrial biog enesis and stabilization of mitochondrial membrane integrity.