Abstract | OBJECTIVE: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA ( mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN). METHODS: A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function. RESULTS: Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme. CONCLUSIONS: We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy.
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Authors | Robert D S Pitceathly, Sinéad M Murphy, Ellen Cottenie, Annapurna Chalasani, Mary G Sweeney, Cathy Woodward, Ese E Mudanohwo, Iain Hargreaves, Simon Heales, John Land, Janice L Holton, Henry Houlden, Julian Blake, Michael Champion, Frances Flinter, Stephanie A Robb, Rupert Page, Michael Rose, Jacqueline Palace, Carol Crowe, Cheryl Longman, Michael P Lunn, Shamima Rahman, Mary M Reilly, Michael G Hanna |
Journal | Neurology
(Neurology)
Vol. 79
Issue 11
Pg. 1145-54
(Sep 11 2012)
ISSN: 1526-632X [Electronic] United States |
PMID | 22933740
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- DNA, Mitochondrial
- MT-ATP6 protein, human
- Mitochondrial Proton-Translocating ATPases
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Topics |
- Adolescent
- Adult
- Aged, 80 and over
- Charcot-Marie-Tooth Disease
(genetics, physiopathology)
- Child
- DNA, Mitochondrial
- Female
- Genotype
- Hereditary Sensory and Motor Neuropathy
(genetics, physiopathology)
- Humans
- Male
- Middle Aged
- Mitochondrial Proton-Translocating ATPases
(genetics)
- Mutation
- Pedigree
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