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Evidence from one family has, at last, pinpointed the cause of dominant optic atrophy (DOA) as an insufficiency in the OPA 1 gene. Previously, whether the disease arose through abnormal functioning of altered proteins or insufficiency was just speculation.
One Australian family with DOA was studied in which no OPA 1 gene mutation had been identified. The ocular signs in the family members were typical of DOA of varying severity. The researchers genotyped the chromosomal DNA from as many of the family as possible with 12 microsatellite markers surrounding the OPA 1 gene and found that three flanking the gene were present as single alleles. After ruling out other causes it was clear the deletion of 560–860 kb DNA, resulting in the loss of one allele of OPA 1, was linked to DOA.
Fluorescence in situ hybridisation (FISH) was performed on metaphase chromosomes of three family members, with cloned OPA 1 c DNA as the probe. The results confirmed that one copy of the OPA 1 gene had been lost in the one affected member and one carrier, but not in the unaffected (control) member.
DOA is the commonest autosomal dominant inherited optic neuropathy. Most families with the disease have altered DNA in chromosome 3q28 (OPA 1), and more than 60 mutations have been identified at this locus. The researchers comment,” haploinsufficiency of the OPA 1 protein is the cause of disease in this family and, in all likelihood, in other DOA families with truncated or mutated OPA 1 alleles.”