Identification of a Novel OPA1 Mutation in a Large Family With a Severe Dominant Optic Atrophy Phenotype

Abstract

Abstract: : Purpose: Dominant optic atrophy (DOA) is a degenerative disease of the optic nerve with autosomal dominant inheritance which causes decreased visual acuity in early childhood. Recently, the disease-causing gene for this disorder (OPA1) was identified. In this study, a large pedigree affected with a severe form of DOA was screened for the presence of disease-causing mutations in the OPA1 gene. Methods: Fifty-six members of a DOA pedigree were studied. Most affected members of this family experienced visual loss (20/40 or poorer) in the first decade of life and most (9/16 eyes) progressed to 20/800 or poorer vision by age 60. Twenty-seven clinically affected family members; 5 obligate carriers; 26 siblings; and 9 spouses were included in this study. DNA was prepared from the blood of study subjects and screened for mutations in the coding sequence of the OPA1 gene using SSCP analysis. Automated sequencing was used to identify the sequence variations detected by SSCP analysis. Results: Two sequence variations, LEU396ARG and ALA536ALA were identified in the proband of the DOA pedigree. The LEU396ARG mutation was identified in all twenty-seven affected family members as well as in all five obligate carriers. The LEU396ARG mutation was not identified in any control subjects. The overall penetrance of the LEU396ARG mutation in this family was 77%. Conclusion: A novel OPA1 mutation (LEU396ARG) is associated with a severe phenotype of DOA.

Keywords: 420 genetics • 480 mutations • 476 molecular biology