Clonal expansion of mitochondrial DNA with multiple deletions in autosomal dominant progressive external ophthalmoplegia

被引:73
作者
Moslemi, AR
Melberg, A
Holme, E
Oldfors, A
机构
[1] SAHLGRENS UNIV HOSP,DEPT PATHOL,S-41345 GOTHENBURG,SWEDEN
[2] SAHLGRENS UNIV HOSP,DEPT CLIN CHEM,S-41345 GOTHENBURG,SWEDEN
[3] UNIV UPPSALA HOSP,DEPT NEUROL,S-75185 UPPSALA,SWEDEN
关键词
D O I
10.1002/ana.410400506
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Sporadic progressive external ophthalmoplegia and Kearns-Sayre syndrome are usually associated with single large-scale mitochondrial DNA deletions in muscle. In progressive external ophthalmoplegia with autosomal dominant inheritance, multiple mitochondrial DNA deletions have been reported. We studied several members of a Swedish family with autosomal dominant progressive external ophthalmoplegia and multiple mitochondrial DNA deletions by polymerase chain reaction analysis of single muscle fibers and by in situ hybridization, combined with enzyme histochemical analysis. Muscle fiber segments with deficiency of cytochrome c oxidase, which is partially encoded by mitochondrial DNA, had accumulated mitochondrial DNA with deletions and showed reduced levels of wild-type mitochondrial DNA. The deletions varied between individual muscle fibers. There was one predominant deletion in each cytochrome c oxidase-deficient muscle fiber segment. Sequencing of the deletion breakpoints showed that most but not all of the deletions were flanked by direct repeats. Young, clinically affected individuals of this family without limb muscle symptoms did not show mitochondrial DNA deletions or cytochrome c oxidase-deficient muscle fibers. Our results indicate that a nuclear factor predisposes to the development of somatic multiple mitochondrial DNA deletions. Mitochondrial DNA with multiple different deletions shows clonal expansion, which leads to mitochondrial myopathy with ragged-red fibers and muscle weakness.
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页码:707 / 713
页数:7
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