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NJ Marchbank, JP Leek, JE Craig, M Toohey, AJ Churchill, DA Mackey, AF Markham, C Toomes, CF Inglehearn; A Dominant Optic Atrophy Family with a Microdeletion at 3q28 Encompassing the OPA1 Gene: Evidence that Haploinsufficiency of OPA1 is the Cause of Disease . Invest. Ophthalmol. Vis. Sci. 2002;43(13):818.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The gene mutated in dominant optic atrophy (DOA) linked to chromosome 3q28 (OPA1) was recently identified. In order to determine the mutation spectrum of OPA1 in DOA, we and others have previously screened the 28 coding exons and their flanking splice sites in large patient cohorts. The purpose of this study was to determine the cause of pathology in a family, with typical features of DOA, in which no mutation was found in the coding sequence or the splice junctions of OPA1. Methods: (1) All available family members were genotyped for microsatellite markers surrounding the OPA1 gene and for three intragenic OPA1 single nucleotide polymorphisms (SNPs). (2) Fluorescent in situ hybridisation (FISH) studies were performed on metaphase chromosomes from selected family members using cloned OPA1 cDNA and bacterial artificial chromosomes (BACs) as probes. Results: Genotyping identified a deletion that segregated in the family. The deletion was found within a region flanked by markers D3S3669 and D3S3562 which encompass the OPA1 gene. The loss of one complete copy of OPA1 in affected family members was demonstrated by FISH analysis using cloned OPA1 cDNA as a probe. Further FISH studies are underway to determine the breakpoints of this deletion, the size of which is estimated to be 560-860 kb. Conclusion: This is the first report of a DOA family with a microdeletion at 3q28 encompassing the OPA1 gene. Our findings suggest that haploinsufficiency, rather than aberrant function of mutated proteins, is the cause of disease in DOA patients with mutations in the OPA1 gene.
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