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Lookup NU author(s): Dr Kyle Thompson, Dr Charlotte Alston, Dr Langping He, Professor Bobby McFarlandORCiD, Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Thompson K, Majd H, Dallabona C, Reinson K, King MS, Alston CL, He LP, 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, Õunap K, Elpeleg O, Ferrero I, McFarland R, Kunji ERS, Taylor RW
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2016
Volume: 99
Issue: 4
Pages: 860-876
Print publication date: 06/10/2016
Online publication date: 29/09/2016
Acceptance date: 18/08/2016
Date deposited: 08/12/2016
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: http://dx.doi.org/10.1016/j.ajhg.2016.08.014
DOI: 10.1016/j.ajhg.2016.08.014
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