ELECTRONIC LETTER OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract

H ereditary optic atrophy is a generic term that refers to a heterogeneous group of genetic disorders for which several modes of inheritance have been described. The most common forms of optic atrophy are autosomal dominant optic atrophy (ADOA, OMIM 165500) and Leber’s hereditary optic neuropathy (LHON, OMIM 53500). ADOA, which generally starts in childhood, is characterised by a progressive decrease in visual acuity, blue-yellow dyschromatopsia, loss of sensitivity in the central visual field, and optic nerve pallor. Mutations in the optic atrophy 1 (OPA1) gene, located on chromosome 3q28–q29, are implicated in about 60–80% of the cases of ADOA. OPA1 encodes for a mitochondrial dynamin related protein. This protein, anchored to the mitochondrial inner membrane, contributes to mitochondrial structure and biogenesis. 6 A second gene involved in ADOA, not yet identified, has been mapped to chromosome 18q (OPA4, OMIM 605293). LHON, which is caused by specific mutations in mitochondrial DNA, is inherited maternally. It is characterised by severe bilateral optic atrophy responsible for acute or subacute visual loss, usually starting between the ages of 18 and 35. Other forms of hereditary optic atrophy include X linked optic atrophy (XLAO, OPA2, OMIM 311050) and autosomal recessive optic atrophy (AROA), for which a first locus has recently been mapped to chromosome 8q. Finally, more than 15 disorders—mostly inherited in the autosomal recessive mode—have combined optic atrophy and extraocular anomalies. Among these syndromic optic atrophies, type III 3-methylglutaconic aciduria (MGA) (OMIM 258501), also known as the Costeff syndrome or the optic atrophy plus syndrome, consists of early onset bilateral optic atrophy, later onset spasticity, extrapyramidal signs, and cognitive deficit. Urinary excretion of 3-methyl glutaconic acid and increased plasma 3-methylglutaric acid levels are the hallmarks of MGA. Linkage analyses, undertaken in MGA families originating from inbred Iraqi-Jewish populations, allowed the mapping of the disease causing gene to chromosome 19q13.2–q13.3, close to the gene responsible for myotonic dystrophy. The gene responsible for MGA, namely optic atrophy 3 (OPA3), has since been identified. Until now, only two mutations in OPA3 have been reported in studies covering nine families affected by type III MGA. 15 Here we report two missense mutations in OPA3 in two families affected by autosomal dominant optic atrophy and cataract (ADOAC), a disease first described by Garcin et al in 1961 (OMIM 165300). Our results indicate that OPA3, encoding a protein in the mitochondrial inner membrane, is responsible for autosomal recessive as well as autosomal dominant optic atrophies. Key points