Deletion of the OPA1 gene in a dominant optic atrophy family: evidence that haploinsufficiency is the cause of disease.

Dominant optic atrophy (DOA) is the most common form of autosomally inherited optic neuropathy. The disease typically presents in childhood with slow bilateral loss of visual acuity, visual field defects, abnormal colour discrimination, and pallor of the optic discs. The majority of DOA families published to date have shown linkage to a major locus on chromosome 3q28 (OPA1). The OPA1 gene was recently identified and found to encode a ubiquitously expressed, dynamin related GTPase. 3 In order to determine the mutation spectrum of OPA1 in DOA, we and others have screened the coding exons and their flanking splice sites in large patient cohorts. Over 60 different mutations have been reported, most of which are specific to individual families. It has been speculated that haploinsufficiency is the cause of disease, but to date there has been no evidence to prove that this mechanism, rather than aberrant function of mutated proteins, is responsible for the disease.