Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number.

TitleRecurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number.
Publication TypeJournal Article
Year of Publication2016
AuthorsThompson, K, Majd, H, Dallabona, C, Reinson, K, King, MS, Alston, CL, He, L, Lodi, T, Jones, SA, Fattal-Valevski, A, Fraenkel, ND, Saada, A, Haham, A, Isohanni, P, Vara, R, Barbosa, IA, Simpson, MA, Deshpande, C, Puusepp, S, Bonnen, PE, Rodenburg, RJ, Suomalainen, A, Ounap, K, Elpeleg, O, Ferrero, I, McFarland, R, Kunji, ERS, Taylor, RW
JournalAm J Hum Genet
Date Published2016 10 06
KeywordsAdenine Nucleotide Translocator 1, Adenosine Diphosphate, Adenosine Triphosphate, Age of Onset, Arylamine N-Acetyltransferase, Child, Child, Preschool, DNA Copy Number Variations, DNA, Mitochondrial, Electron Transport, Exome, Female, Genes, Dominant, Humans, Infant, Infant, Newborn, Isoenzymes, Male, Mitochondrial Diseases, Muscle, Skeletal, Mutation

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 mitochondrial respiratory chain deficiencies associated with a marked loss of mitochondrial 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 mitochondrial 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 mitochondrial 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 mitochondrial 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.

Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2016.08.014
PubMed ID27693233
PubMed Central IDPMC5065686
Grant ListMC_U105663139 / / Medical Research Council / United Kingdom
NIHR-HCS-D12-03-04 / / Department of Health / United Kingdom
R01 NS083726 / NS / NINDS NIH HHS / United States