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M. Votruba, D. Thiselton, S. Aijaz, A. Moore, S. Bhattacharya; A Large Dominant Optic Atrophy Family with a Severe Phenotype Excludes the OPA1 and OPA4 Loci: Evidence of Further Genetic Heterogeneity . Invest. Ophthalmol. Vis. Sci. 2003;44(13):632.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Autosomal dominant optic atrophy (ADOA) has been linked to two genetic loci, the first of which on chromosome 3q28 (OPA1: MIM165500) appears to be the predominant locus. A single large kindred of German descent has been mapped to a locus on chromosome 18q12.2-q12, designated OPA4 (MIM). We identified a large pedigree of English descent, which manifested a severe phenotype of visual loss and optic atrophy and undertook linkage analysis and mutation detection. Methods: Linkage analysis was performed using a panel of fourteen polymorphic microsatellite markers from chromosome 3q28 and four markers from chromosome 18q12.2-q12. A detailed haplotype was drawn up for both loci. PCR-based sequence analysis of the genes OPA1 and OPA3 was carried out. Results: This family shows no evidence of genetic linkage to the two published loci for ADOA. Markers on chromosome 3q28 show exclusion to 10 cM with a Lod score of -1.98 at marker D3S3642, with a recombination fraction of 0.1. On chromosome 18q12.2-q12 a Lod score of –2.91 was obtained with marker D18S1137 with a recombinant fraction of 0.1. This data was reflected in the fine mapping and haplotype analysis performed at both of these loci. Subsequently, OPA1 locus exclusion was further confirmed by the finding of no OPA1 mutation in DNA samples from this pedigree by PCR sequence-based analysis. Mutation in the OPA3 gene was also excluded by sequence analysis of the coding exons. Conclusion: This family represents a novel ADOA locus and provides further evidence for genetic heterogeneity in ADOA.
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