OPA1 Mutations and Clinical Phenotype in Japanese Patients with Dominant Optic Atrophy

Abstract

Abstract: : Purpose: Autosomal dominant optic atrophy (DOA) is characterized by symmetric optic atrophy associated with reduced corrected visual acuity, central or centrocaecal stroma, and color vision disturbances. The disease is genetically heterogeneous, and the OPA1 gene has been identified as a causative gene. The aim of this study was to determine mutations of the OPA1 gene in Japanese patients with DOA and to describe the clinical features of the patients. Methods: Nineteen separate Japanese families with optic atrophy were examined. Seven families had an autosomal dominant inheritance pattern, and 11 probands were considered to be sporadic from their family histories. The inheritance pattern could not be determined in one family. Genomic DNA was extracted from leukocytes of the peripheral blood, and exons 1 through 28 of the OPA1 gene were amplified by polymerase chain reaction and directly sequenced. A complete ophthalmologic examination was performed including best–corrected visual acuity, visual fields, slit–lamp and fundus examination, fundus photography, and color vision testing. Results: Ten heterozygous mutations in the OPA1 gene were identified in 12 Japanese families with DOA. Eight of the mutations were novel. Six of the seven autosomal dominant families as well as 5 out of 11 the sporadic probands had a mutation. Family examination of 2 sporadic probands revealed that the true hereditary pattern in the families was autosomal dominant. The identified mutations included five deletions/insertions, three nonsense, one splice site, and one missense mutations. The frequently–detected mutation (c.2708delTTAG) in Caucasians, was found in three families. Clinically, the severity varied considerably from legally blind to asymptomatic patients. Conclusions: OPA1 gene mutations are causative in most Japanese families with DOA. Sporadic cases with optic atrophy are caused by OPA1 mutations at a relatively high frequency in Japanese population.

Keywords: mutations • optic disc • degenerations/dystrophies