The OPA1 gene mutations in patients with autosomal dominant optic atrophy and associated morphological and physiological changes.

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The OPA1 gene was examined in Japanese patients with autosomal dominant optic atrophy (ADOA), and 11 different heterozygous mutations in the gene were detected in 13 unrelated families. We detected an OPA1 mutation in 8/9 familial cases with optic atrophy indicating that the OPA1 gene mutations are causative in most familial cases with ADOA in Japanese. We detected a mutation in 5/10 cases that were initially considered to be sporadic from their family histories, indicating that sporadic cases with optic atrophy may also be frequently caused by OPA1 mutations in Japanese population. The identified mutations included five deletions/insertions, four nonsense, one splice site, and one missense mutations. Because most of the mutations were truncative mutations or splice site mutations, the mechanism of haplo-insufficiency was suggested to be involved in the pathogenesis of ADOA. The most common mutation in Caucasians (c.2708_2711delTTAG) was found in three unrelated families, suggesting th … More at it is a mutational hot spot.The morphological changes in the macular area were determined in patients with the OPA1 mutations. The thickness of the retinal nerve fiber layer (RNFL) in the macular area was significantly thinner in the ADOA patients than that in controls. The thickness of the layer including the ganglion cell layer was also significantly thinner in the patients. The thickness of the outer retina was not significantly different between the ADOA patients and normal controls, thus we confirmed that the inner retina is the main area of the retina altered morphologically by this disease.The amplitudes of photopic negative response (PhNR) in full-field electroretinogram (ERG), which are considered to reflect the function of inner retina, were significantly smaller in the patients ADOA than those in controls. Although it is generally believed that patients with ADOA have normal b-wave amplitudes in full-field ERG, we found a case of optic atrophy associated with an OPA1 mutation whose b-wave was reduced showing negative ERG waveform. We could find no correlation between clinical severity and genotype. Less