Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy 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 alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent 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 mitochondrial membrane integrity.
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We thank all clinicians who referred patients; the patients and their family members for participation; T. Nagase for the KIAA0567 full-length cDNA clone; B. Jurklies and H. Wilhelm for the collection of additional families; C. Willis for help with UK pedigree and sample collection; B. Baumann and S. Tippmann for technical assistance; S. Kohl for help with the SSCP analysis; and C. Pusch for various technical and computational advice. This work was supported by The Wellcome Trust, UK Project Grant 056047 (M.V., S.S.B. and A.M.), The Guide Dogs for the Blind Association, The Joint British Council/DAAD Academic Research Collaboration Programme ARC 1074 (M.V. & B.W.), and a grant from the Bundesministerium fuer Bildung und Forschung (01 KS 9602) and the Interdisziplinaeres Zentrum fuer Klinische Forschung Tuebingen (B.W.). C.A. is supported by a fellowship of the Deutsche Forschungsgemeinschaft.
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Alexander, C., Votruba, M., Pesch, U. et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26, 211–215 (2000) doi:10.1038/79944
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