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A Homozygous Splice Site Mutation in SLC25A42, Encoding the Mitochondrial Transporter of Coenzyme A, Causes Metabolic Crises and Epileptic Encephalopathy

  • Arcangela Iuso
  • Bader Alhaddad
  • Corina Weigel
  • Urania Kotzaeridou
  • Elisa Mastantuono
  • Thomas Schwarzmayr
  • Elisabeth Graf
  • Caterina Terrile
  • Holger Prokisch
  • Tim M. Strom
  • Georg F. Hoffmann
  • Thomas Meitinger
  • Tobias B. HaackEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 44)

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.

Notes

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.

Supplementary material

477624_1_En_115_MOESM1_ESM.zip (90 kb)
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)
477624_1_En_115_MOESM2_ESM.pdf (3 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)
477624_1_En_115_MOESM3_ESM.xlsx (14 kb)
Supplementary Table 1 Clinical and genetic findings in SLC25A42-affected individuals (Modified from Almannai et al. 2018) (XLSX 14 kb)
477624_1_En_115_MOESM4_ESM.xlsx (18 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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Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • Arcangela Iuso
    • 1
    • 2
  • Bader Alhaddad
    • 1
  • Corina Weigel
    • 3
  • Urania Kotzaeridou
    • 4
  • Elisa Mastantuono
    • 1
    • 2
  • Thomas Schwarzmayr
    • 2
  • Elisabeth Graf
    • 2
  • Caterina Terrile
    • 2
  • Holger Prokisch
    • 1
    • 2
  • Tim M. Strom
    • 1
    • 2
  • Georg F. Hoffmann
    • 4
  • Thomas Meitinger
    • 1
    • 2
  • Tobias B. Haack
    • 1
    • 5
    Email author
  1. 1.Institute of Human Genetics, Technische Universität MünchenMunichGermany
  2. 2.Institute of Human Genetics, Helmholtz Zentrum MünchenNeuherbergGermany
  3. 3.Department of PaediatricsUniversity of Erlangen-NürnbergErlangenGermany
  4. 4.Division of Neuropediatrics and Pediatric Metabolic Medicine, Department of General PediatricsUniversity Hospital HeidelbergHeidelbergGermany
  5. 5.Institute of Medical Genetics and Applied Genomics, University of TübingenTübingenGermany

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