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Molecular evidence from two unrelated French families has shown that autosomal dominant optic atrophy with cataract (ADOAC) is caused by an affected OPA3 gene, formerly associated only with autosomal recessive forms of optic atrophy (OA). This adds yet another type of OA to those already associated with mitochondrial abnormalities.
Affected members of both families had ADOAC associated with one of two new missense mutations in OPA3, which codes for an inner mitochondrial membrane protein. This was a 277G→A mutation in exon 2 in one family and a 313C→G mutation in the other. The mutations occurred only in affected family members, not in healthy relatives or control chromosomes. Skin fibroblasts from one family member with the 277G→A mutation were much more sensitive to staurosporin, which induced cell death in 35% versus only 5% of fibroblasts from a healthy control. Various tests in this family member excluded type III 3-methylglutaconic aciduria (MGA), which shows autosomal recessive OA and is a syndromic OA linked to the only previously known mutations in the OPA3 gene.
The families were from an earlier series of families with ADOA previously identified as negative for the OPA1 gene, the commonest gene associated with the condition. The OPA3 gene was directly sequenced in 11 affected family members, their 10 healthy relatives, and 400 controls.
OPA1 gene mutations account for 60–80% ADOA. Two OPA3 mutations have been identified in type III MGA, but there are more than fifteen other disorders, mostly autosomal recessive, which combine OA with non-optic abnormalities.
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