Mutation of the mitochondrial carrier SLC25A42 causes a novel form of mitochondrial myopathy in humans

• Published in: Human genetics Vol. 135; no. 1; pp. 21 - 30
• Main Authors: Shamseldin, Hanan E., Smith, Laura L., Kentab, Amal, Alkhalidi, Hisham, Summers, Brady, Alsedairy, Haifa, Xiong, Yong, Gupta, Vandana A., Alkuraya, Fowzan S.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2016; Springer; Springer Nature B.V
• Subjects: Acidosis; Adenine Nucleotide Translocator 1 - genetics; Adolescent; Analysis; Animals; Biomedical and Life Sciences; Biomedicine; Danio rerio; Enzymes; Female; Gene Function; Genes; Genetic aspects; Genomes; Genomics; Human Genetics; Humans; Male; Metabolic Diseases; Mitochondrial Myopathies - genetics; Models, Animal; Molecular Medicine; Mutation; Original Investigation; Pedigree; RNA; RNA, Messenger - genetics; Zebrafish; Saudi Arabia; United States > US; Riyadh Saudi Arabia; SLC25A42 Protein; Citrullinemia; Mitochondrial Myopathy; Zebrafish Embryo; Sideroblastic Anemia
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-015-1608-8

Myopathies are heterogeneous disorders characterized clinically by weakness and hypotonia, usually in the absence of gross dystrophic changes. Mitochondrial dysfunction is a frequent cause of myopathy. We report a simplex case born to consanguineous parents who presented with muscle weakness, lactic acidosis, and muscle changes suggestive of mitochondrial dysfunction. Combined autozygome and exome analysis revealed a missense variant in the SLC25A42 gene, which encodes an inner mitochondrial membrane protein that imports coenzyme A into the mitochondrial matrix. Zebrafish slc25a42 knockdown morphants display severe muscle disorganization and weakness. Importantly, these features are rescued by normal human SLC25A42 RNA, but not by RNA harboring the patient’s variant. Our data support a potentially causal link between SLC25A42 mutation and mitochondrial myopathy in humans.