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SP Suriyapperuma, A Child, G Brice, SP Desai, M Sarfarazi; Identification of an OPA1 truncating mutation in a family with Optic Atrophy . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2393.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Mutations in a nuclear gene encoding a mitochondrial dynamin-related GTPase has been found to be responsible for Autosomal Dominant Optic Atrophy linked to chromosome 3q28. We have previously mapped a 4-generation English family to this region and refined the OPA1 locus to less than 2 cM (Ophthal. Genet. 1997; 18:1-6). The purpose of this study was to identify the causative mutation in this British family. Methods: The family consists of a total of 29 subjects, 10 of whom are affected. A total of 8 affected and 14 normal subjects were available for this study. The clinical phenotype consisted of moderate to severe decrease of visual acuity, insidious onset in early childhood, central scotoma and characteristic atrophic appearance of the optic disc. An affected male segregating for the entire OPA1 region and his normal daughter was selected for screening. Genomic DNA was amplified using intronic primers for 28 exons in OPA1 gene as described previously. Amplified fragments were screened by SSCP and the observed band shifts were verified by direct sequencing. After mutation was identified, its’ segregation in 22 members of the family was studied by SSCP analysis. Results: Two band shifts in the affected subject as compared to the normal control were identified by SSCP analysis. One of them was a polymorphism in the intron 16 (35th position prior to the exon 17, a change of A to T). The causative mutation was found in exon 27, codon 934, changing Gln to a stop codon (Q934X) thus, truncating the protein by 27 amino acids. The SSCP band corresponding to the mutated allele was present in 8 affected individuals and one gene carrier, but was absent in all of other normal subjects. Conclusion: We have identified the disease causing mutation in an English family with Optic atrophy. The mutation lies within the coil-coil domain and in the C terminus of the protein. A haploinsufficiency is expected to be responsible for the clinical phenotype presented in this family.
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