期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 99, 期 4, 页码 860-876出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2016.08.014
关键词
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资金
- Wellcome Trust [096919/Z/11/Z]
- MRC Centre for Neuromuscular Diseases [G0601943]
- Lily Foundation
- UK NHS Highly Specialised Rare Mitochondrial Disorders of Adults and Children Service in Newcastle upon Tyne
- NIHR/CSO Healthcare Science Research Fellowship from the National Institute for Health Research [NIHR-HCS-D12-03-04]
- Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' NHS Foundation Trust in partnership with the King's College London
- Medical Research Council UK [MC_U105663139]
- Fondazione Telethon (Italy) [GGP15041]
- Estonian Science Foundation [8175, PUT355]
- Jane and Aatos Erkko Foundation
- Sigrid Juselius Foundation
- Academy of Finland
- Helsinki University Hospital Funds
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health [R01NS083726]
- Medical Research Council [MC_U105663139] Funding Source: researchfish
- National Institute for Health Research [NIHR-HCS-D12-03-04] Funding Source: researchfish
- MRC [MC_U105663139] Funding Source: UKRI
Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations. All affected individuals presented at birth, were ventilator dependent and, where tested, revealed severe combined mitochondria' respiratory chain deficiencies associated with a marked loss of mitochondria' DNA copy number in skeletal muscle. Strikingly, an identical c.239G>A (p.Arg80His) mutation was present in four of the seven subjects, and the other three case subjects harbored the same c.703C>G (p.Arg235Gly) mutation. Analysis of skeletal muscle revealed a marked decrease of AAC1 protein levels and loss of respiratory chain complexes containing mitochondria' DNA-encoded subunits. We show that both recombinant AAC1 mutant proteins are severely impaired in ADP/ATP transport, affecting most likely the substrate binding and mechanics of the carrier, respectively. This highly reduced capacity for transport probably affects mitochondria' DNA maintenance and in turn respiration, causing a severe energy crisis. The confirmation of the pathogenicity of these de novo SLC25A4 mutations highlights a third distinct clinical phenotype associated with mutation of this gene and demonstrates that early-onset mitochondria' disease can be caused by recurrent de novo mutations, which has significant implications for the application and analysis of whole-exome sequencing data in mitochondrial disease.
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