OBJECTIVE: To map the gene responsible for autosomal dominant progressive external opthalmoplegia. BACKGROUND: The pathogenesis of progressive external ophthalmoplegia (PEO) can be associated with multiple deletions of mitochondrial DNA (mtDNA). PEO may show autosomal dominant (adPEO) or autosomal recessive (arPEO) patterns of inheritance, indicating that the genetic defect has a Mendelian basis and most likely involves a nuclear gene encoding a protein that interacts with the mitochondrial genome. adPEO is heterogeneous genetically, and thus far disease loci have been identified on chromosomes 3 and 10. The locus on chromosome 10q23-q25 was assigned by linkage analysis in a single Finnish family. METHODS: Samples from a large Pakistani family with adPEO, in which clinical symptoms are bilateral ptosis, limitations of eye movements, and varying degrees of proximal muscle weakness, were collected. Muscle biopsy and mtDNA rearrangement analysis was used to confirm the diagnosis. Genomewide linkage analysis was set up using a set of 391 microsatellite markers. RESULTS: The muscle biopsy from an affected member showed ragged red fibers, increased succinic dehydrogenase staining, lack of cytochrome oxidase activity, and multiple deletions of mtDNA. The disease locus was mapped to 10q23.31-q25.1 by linkage analysis, and a maximum lod score of 5.72 was obtained with D10S1267. CONCLUSION: By analysis of meiotic recombinations in affected individuals, the critical region was restricted to the 7-cM interval between D10S198 and D10S1795.
OBJECTIVE: To map the gene responsible for autosomal dominant progressive external opthalmoplegia. BACKGROUND: The pathogenesis of progressive external ophthalmoplegia (PEO) can be associated with multiple deletions of mitochondrial DNA (mtDNA). PEO may show autosomal dominant (adPEO) or autosomal recessive (arPEO) patterns of inheritance, indicating that the genetic defect has a Mendelian basis and most likely involves a nuclear gene encoding a protein that interacts with the mitochondrial genome. adPEO is heterogeneous genetically, and thus far disease loci have been identified on chromosomes 3 and 10. The locus on chromosome 10q23-q25 was assigned by linkage analysis in a single Finnish family. METHODS: Samples from a large Pakistani family with adPEO, in which clinical symptoms are bilateral ptosis, limitations of eye movements, and varying degrees of proximal muscle weakness, were collected. Muscle biopsy and mtDNA rearrangement analysis was used to confirm the diagnosis. Genomewide linkage analysis was set up using a set of 391 microsatellite markers. RESULTS: The muscle biopsy from an affected member showed ragged red fibers, increased succinic dehydrogenase staining, lack of cytochrome oxidase activity, and multiple deletions of mtDNA. The disease locus was mapped to 10q23.31-q25.1 by linkage analysis, and a maximum lod score of 5.72 was obtained with D10S1267. CONCLUSION: By analysis of meiotic recombinations in affected individuals, the critical region was restricted to the 7-cM interval between D10S198 and D10S1795.
Authors: C Fratter; G S Gorman; J D Stewart; M Buddles; C Smith; J Evans; A Seller; J Poulton; M Roberts; M G Hanna; S Rahman; S E Omer; T Klopstock; B Schoser; C Kornblum; B Czermin; B Lecky; E L Blakely; K Craig; P F Chinnery; D M Turnbull; R Horvath; R W Taylor Journal: Neurology Date: 2010-05-18 Impact factor: 9.910