Novel mutations in the OPA1 gene and associated clinical features in Japanese patients with optic atrophy

Purpose: Autosomal dominant optic atrophy (ADOA) is characterized by symmetrical bilateral optic atrophy associated with reduced corrected visual acuity (VA), central or centrocecal scotoma, and color vision disturbances. The disease is genetically heterogeneous, and the OPA1 gene has been identified as the only causative gene. The aims of this study were to identify and report mutations in the OPA1 gene in Japanese patients with ADOA and to describe the clinical features associated with the mutations. Design: Molecular genetic study and observational case reports. Participants: Nine unrelated Japanese families with optic atrophy and 8 isolated cases of optic atrophy. Methods: Genomic DNA was extracted from peripheral leukocytes, and all exons containing the open reading frame of the OPA1 gene and the flanking intron splice sites were sequenced directly. Complete ophthalmologic examinations were performed. Main Outcome Measures: Direct sequencing of the OPA1 gene and clinical evaluations including VA, visual field, color vision, and disc appearance. Results: Ten different heterozygous mutations, including 6 novel mutations, were detected in the OPA1 gene. The identified mutations included 5 deletions/insertions (c.2061delA, c.2098_2103delCTTAAA, c.2538insT, c.2591 insC, and c.2708_2711delTTAG), 4 nonsense mutations (c.112C > T [p.R38X], c.181C > T [p.061X], c.946A > T [p.R316X], and c.2713C > T [p.R905X]), and 1 missense mutation (c.1635C > A [p.S545R]). The most common mutation in Caucasians (c.2708_2711 delTTAG) was found in 3 unrelated families, suggesting that it is a mutational hot spot. We detected an OPA1 mutation in 8 of 9 familial cases of optic atrophy and in 4 of 8 cases that were initially considered to be sporadic from the patients' family histories. Examinations of family members of 2 sporadic probands revealed the existence of other family members with the OPA1 mutations whose phenotype was very mild or within normal limits. This indicates that patients with ADOA sometimes seem to be sporadic because of the extensive variation in the phenotype or, alternatively, a low penetrance of ADOA. Conclusions: OPA1 gene mutations are causative in most familial cases of ADOA in Japanese. Sporadic cases of optic atrophy frequently may be caused by OPA1 mutations in the Japanese population. Molecular genetic examinations are useful in determining the hereditary patterns in some cases of optic atrophy.