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CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature

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HUMAN MOLECULAR GENETICS
卷 -, 期 -, 页码 -

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OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddad161

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mitochondria; neurodegeneration; mtDNA deletions; mitochondrial DNA; CHCHD10

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Mutations in the mitochondrial intermembrane space protein CHCHD10 can cause different clinical phenotypes. In this study, we investigated whether the mutations lead to mitochondrial DNA deletions and found that the deletion levels were higher in mutant mice compared to wild-type mice, depending on the Chchd10 genotype and age. We also observed that the spinal cord was less prone to mtDNA deletions. Furthermore, the mutations led to the accumulation of a novel set of deletions characterized by shorter direct repeats flanking the deletion breakpoints. These findings suggest that tissue-specific deletions induced by Chchd10 mutations may contribute to the clinical phenotype in humans.
Mutations affecting the mitochondrial intermembrane space protein CHCHD10 cause human disease, but it is not known why different amino acid substitutions cause markedly different clinical phenotypes, including amyotrophic lateral sclerosis-frontotemporal dementia, spinal muscular atrophy Jokela-type, isolated autosomal dominant mitochondrial myopathy and cardiomyopathy. CHCHD10 mutations have been associated with deletions of mitochondrial DNA (mtDNA deletions), raising the possibility that these explain the clinical variability. Here, we sequenced mtDNA obtained from hearts, skeletal muscle, livers and spinal cords of WT and Chchd10 G58R or S59L knockin mice to characterise the mtDNA deletion signatures of the two mutant lines. We found that the deletion levels were higher in G58R and S59L mice than in WT mice in some tissues depending on the Chchd10 genotype, and the deletion burden increased with age. Furthermore, we observed that the spinal cord was less prone to the development of mtDNA deletions than the other tissues examined. Finally, in addition to accelerating the rate of naturally occurring deletions, Chchd10 mutations also led to the accumulation of a novel set of deletions characterised by shorter direct repeats flanking the deletion breakpoints. Our results indicate that Chchd10 mutations in mice induce tissue-specific deletions which may also contribute to the clinical phenotype associated with these mutations in humans.

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