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

Am J Hum Genet. 2016 Oct 6;99(4):860-876. doi: 10.1016/j.ajhg.2016.08.014.

Kyle Thompson ¹, Homa Majd ², Cristina Dallabona ³, Karit Reinson ⁴, Martin S King ², Charlotte L Alston ¹, Langping He ¹, Tiziana Lodi ³, Simon A Jones ⁵, Aviva Fattal-Valevski ⁶, Nitay D Fraenkel ⁷, Ann Saada ⁸, Alon Haham ⁹, Pirjo Isohanni ¹⁰, Roshni Vara ¹¹, Inês A Barbosa ¹², Michael A Simpson ¹², Charu Deshpande ¹³, Sanna Puusepp ⁴, Penelope E Bonnen ¹⁴, Richard J Rodenburg ¹⁵, Anu Suomalainen ¹⁶, Katrin Õunap ⁴, Orly Elpeleg ¹⁷, Ileana Ferrero ³, Robert McFarland ¹, Edmund R S Kunji ², Robert W Taylor ¹⁸

Affiliations

1 Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
2 The Medical Research Council, Mitochondrial Biology Unit, Cambridge Biomedical Campus, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
3 Department of Life Sciences, University of Parma, Parco Area delle Scienze 11A, Parma 43124, Italy.
4 Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, 51014 Tartu, Estonia; Department of Genetics, United Laboratories, Tartu University Hospital, 51014 Tartu, Estonia.
5 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, St Marys Hospital, Oxford Road, Manchester M13 9WL, UK.
6 Paediatric Neurology Unit, "Dana" Children Hospital, Tel Aviv Sourasky Medical Centre, Sackler Faculty of Medicine, Tel Aviv University, 64239 Tel Aviv, Israel.
7 Department of Respiratory Rehabilitation, Alyn Hospital, Jerusalem 91090, Israel.
8 Metabolic Laboratory Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
9 Neonatal Intensive Care Unit, "Lis" Maternity Hospital, Tel Aviv Sourasky Medical Centre, 64239 Tel Aviv, Israel.
10 Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland; Department of Pediatric Neurology, Children's Hospital, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland.
11 Department of Paediatric Inherited Metabolic Diseases, Evelina Children's Hospital, London SE1 7EH, UK.
12 Division of Genetics and Molecular Medicine, King's College London School of Medicine, London SE1 9RY, UK.
13 Clinical Genetics Unit, Guys and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.
14 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
15 Radboud Center for Mitochondrial Medicine, Department of Paediatrics, Translational Metabolic Laboratory, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
16 Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland; Department of Neurosciences, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland.
17 The Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
18 Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: robert.taylor@ncl.ac.uk.

PMID: 27693233 DOI: 10.1016/j.ajhg.2016.08.014

Abstract

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.

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