A novel OPA1 mutation in a family with Autosomal Dominant Optic Atrophy

Heading: To identify pathogenic mutations in patients with ADOA, previously excluded for LHON mutations. Background: Autosomal dominant optic atrophy (ADOA), Kjer type, is an inherited primary optic neuropathy that leads to reduced visual acuity. It presents with an insidious onset of variable visual loss, optic nerve pallor, centrocaecal visual field scotoma and colour vision deficit, t-Iistopathological studies suggest that the underlying defect is due to retinal ganglion cells degeneration, as found in Leber Hereditary Optic. Neuropathy (LHHON). Genetic linkage studies localized a dominant optic atrophy gene (OPAl; OMIMI65500) to chromosome 3q28ter. OPAl encodes a large GTPase related to dynanffns, implicated in the fomtafion and the maintenance of the mitochondrial network. Titus, ADOA seems to be due to intpaitment of the mitochondrial function. To date more than 70 mutations in about 250 ADOA patients have been reported in literature. Most of them (90%) are distributed from exons 8 to 28 with the majority in the GTPase domain. In particular almost 50% of the mutations are localized in exons 8, 9, 12 and 27. Methods: Genomic DNA was extracted fi'om leukocytes of two siblings with optic, atrophy. Exons 8, 9, 12 and 27 were amplified by polymerase chain reaction and directly sequenced. Results: One novel nonsense mutation was detected in exon 9, R312Stop, resulting from a C>T transition at position c.934. This sequence variation has not been previously reported. Conclusions: The exon 9 truncative mutation found in this fanffly stress the importance to screen exons 8, 9, 12 and 27. The discovery of new mutations in OPAl leads us to concentrate our efforts on ADOA pathogenesis. The link between OPAl and apoptosis give clues of the possible pathophysiological effect of the mutation that leads to neurodegeneration of the retinal ganglion cells. A full comprehension of tiffs mechanism could help us understanding LHON pathogenesis. In conclusion, can Leber's and Kjer's diseases be considered variation on the same theme?