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E.I. Traboulsi, C. Li, G. Kosmorsky, K. Zhang; Optic Atrophy, Progressive Sensorineural Hearing Loss and Myopia Caused by an R445H OPA1 Mutation . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1826.
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Purpose:One form of dominant optic atrophy is caused by mutations in OPA1, a gene that encodes a dynamin–related GTPase. The R445H mutation in OPA1 has been described on three occasions to cause optic atrophy and deafness. We report an Ohio family in which the same mutation has resulted in this unique phenotype of optic atrophy with progressive myopia and deafness, in the absence of other neurological abnormalities. Methods: Six family members of a two–generation Caucasian family underwent detailed ophthalmic examinations, visual field testing, color vision testing, and audiometric evaluation. Genomic DNA was extracted from blood samples. . Exons of OPA1 were directly sequenced with the Taq Dyedeoxy Terminator Cycle Sequencing Kit (Beckman–Coulter, Fullerton, CA) according to the manufacturer's instructions. Results:,Four family members were affected and 2 were unaffected. Ages ranged from 11 to 44 years. Visual acuity varied from 20/30 to 20/100. Optic nerve pallor was present in all affected individuals. All four affected individuals were myopic and the older three showed progressive increase of their myopia over time and into adulthood. Audiometric data indicated progressive hearing loss from mild to severe in the proband over 11 years. Auditory brain responses were unrecordable in this patient. Genotyping analysis using polymorphic DNA markers D3S2418, D3S2305, D3S3590, and D3S1311 encompassing the OPA1 gene revealed positive linkage, and extended disease haplotype co–segregated with the disease phenotype. Sequencing analysis of the OPA1 gene revealed a missense 1334 G > A mutation in exon 14, resulting in the substitution of a highly conserved arginine by histidine at codon 445 of the GTPase domain of OPA1. This change segregated with the disease phenotype in the study family (Figure 1) and was not found in 200 normal controls. Conclusions:The R445H mutation in OPA1 causes a distincitive combination of optic atrophy and progressive myopia and deafness. This phenotype is likely the result of abnormal mitochondrial function induced by this particular OPA1 mutation.
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