Abstract
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.
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Acknowledgments
We thank the Genotyping and Sequencing Core Facilities at KFSHRC for their technical help. DNA sequencing for molecular cloning was done through the Boston Children’s Hospital IDDRC Molecular Genetics Core, which is supported by National Institutes of Health grant [NIH-P30-HD-18655].
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This work was supported by King Abdulaziz City for Science and Technology [13-BIO1113-20 to FSA], the National Institutes of Health, including the National Institute of Arthritis and Musculoskeletal and Skin Diseases [K01 AR062601 to VAG] and the National Institute of Neurological Disorders and Stroke [F31 NS081928 to LLS], as well as the Charles H. Hood Foundation Child Health Research Grant to VAG.
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H. E. Shamseldin and L. L. Smith have contributed equally.
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Figure S2. Slc25a42 morphants exhibit organized skeletal muscles. (A-C) Whole-mount phalloidin staining of filamentous actin in 3 dpf zebrafish shows normal skeletal muscle organization in both wild-type embryos and slc25a42 morphants. Scale bars: 10 μm. (D-G) Wild-type and morphant embryos display relatively bright birefringence under polarized light microscopy. Note that the curvature of morphants often impairs clear visualization of this feature. (PDF 4608 kb)
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Shamseldin, H.E., Smith, L.L., Kentab, A. et al. Mutation of the mitochondrial carrier SLC25A42 causes a novel form of mitochondrial myopathy in humans. Hum Genet 135, 21–30 (2016). https://doi.org/10.1007/s00439-015-1608-8
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DOI: https://doi.org/10.1007/s00439-015-1608-8