Abstract
SLC25A42 is an inner mitochondrial membrane protein which has been shown to transport coenzyme A through a lipid bilayer in vitro. A homozygous missense variant in this gene has been recently reported in 13 subjects of Arab descent presenting with mitochondriopathy with variable clinical manifestations. By exome sequencing, we identified two additional individuals carrying rare variants in this gene. One subject was found to carry the previously reported missense variant in homozygous state, while the second subject carried a homozygous canonical splice site variant resulting in a splice defect. With the identification of two additional cases, we corroborate the association between rare variants in SLC25A42 and a clinical presentation characterized by myopathy, developmental delay, lactic acidosis, and encephalopathy. Furthermore, we highlight the biochemical consequences of the splice defect by measuring a mild decrease of coenzyme A content in SLC25A42-mutant fibroblasts.
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Acknowledgments
Study funding: TBH was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant #FKZ 01ZX1405C). HP by the E-Rare project GENOMIT (01GM1207) and the EU Horizon 2020 Collaborative Research Project SOUND (633974). AI by the EU project TIRCON.
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Communicated by: Wolfgang Sperl, MD, PhD
Electronic Supplementary Material
Supplementary Fig. 1
Primer sequences (a), PCR conditions (b), and amplicon sizes (bp) of SLC25A42 exons 2–7, 3–7, and 6–7 (TIF 90 kb)
Supplementary Fig. 2
Expression of SLC25A42 in human tissues. Raw read counts and total amount of sequence normalized values (FPKM) indicate an about tenfold lower expression in fibroblasts compared to the brain, muscle, liver, and kidney tissues, respectively. Data were extracted from our in-house database (PDF 3 kb)
Supplementary Table 1
Clinical and genetic findings in SLC25A42-affected individuals (Modified from Almannai et al. 2018) (XLSX 14 kb)
Supplementary Table 2
Compound heterozygous and homozygous variants detected using whole exome sequencing, after applying quality and frequency filters, in Case 1 and 2, respectively (XLSX 17 kb)
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Synopsis
Mutations in SLC25A45 cause epileptic encephalopathy.
Details of the Contributions of Individual Authors
Conceived and designed the work: AI, BA, HP, and TBH. Performed the experiments: AI, CT, and EG. Analyzed and interpreted the clinical and genetic data: CW, UK, EM, TS, TMS, GFH, TM, and TBH. Drafted the article: AI, BA, and TBH. Critically revised the draft: all authors.
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Conflict of Interest
A. Iuso, B. Alhaddad, C. Weigel, U. Kotzaeridou, E. Mastantuono, T. Schwarzmayr, E. Graf, C. Terrile, H. Prokisch, T. M. Strom, G. F. Hoffmann, T. Meitinger, and T. B. Haack declare no conflict of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.
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Written informed consent was obtained from all individuals or caregivers.
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© 2018 Society for the Study of Inborn Errors of Metabolism (SSIEM)
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Iuso, A. et al. (2018). A Homozygous Splice Site Mutation in SLC25A42, Encoding the Mitochondrial Transporter of Coenzyme A, Causes Metabolic Crises and Epileptic Encephalopathy. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 44. JIMD Reports, vol 44. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_115
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DOI: https://doi.org/10.1007/8904_2018_115
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