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Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility

Author

Listed:
  • Yukari Endo

    (Hospital for Sick Children)

  • Linda Groom

    (University of Rochester)

  • Alper Celik

    (Hospital for Sick Children)

  • Natalia Kraeva

    (Malignant Hyperthermia Unit, Department of Anesthesia, Toronto General Hospital)

  • Chang Seok Lee

    (Baylor College of Medicine)

  • Sung Yun Jung

    (Baylor College of Medicine)

  • Lois Gardner

    (University of Leeds)

  • Marie-Anne Shaw

    (University of Leeds)

  • Susan L. Hamilton

    (Baylor College of Medicine)

  • Philip M. Hopkins

    (University of Leeds
    Malignant Hyperthermia Unit, St. James’s University Hospital)

  • Robert T. Dirksen

    (University of Rochester)

  • Sheila Riazi

    (Malignant Hyperthermia Unit, Department of Anesthesia, Toronto General Hospital)

  • James J. Dowling

    (Hospital for Sick Children
    Hospital for Sick Children
    University of Toronto
    University of Toronto)

Abstract

Exertional heat illness (EHI) and malignant hyperthermia (MH) are life threatening conditions associated with muscle breakdown in the setting of triggering factors including volatile anesthetics, exercise, and high environmental temperature. To identify new genetic variants that predispose to EHI and/or MH, we performed genomic sequencing on a cohort with EHI/MH and/or abnormal caffeine-halothane contracture test. In five individuals, we identified rare, pathogenic heterozygous variants in ASPH, a gene encoding junctin, a regulator of excitation-contraction coupling. We validated the pathogenicity of these variants using orthogonal pre-clinical models, CRISPR-edited C2C12 myotubes and transgenic zebrafish. In total, we demonstrate that ASPH variants represent a new cause of EHI and MH susceptibility.

Suggested Citation

  • Yukari Endo & Linda Groom & Alper Celik & Natalia Kraeva & Chang Seok Lee & Sung Yun Jung & Lois Gardner & Marie-Anne Shaw & Susan L. Hamilton & Philip M. Hopkins & Robert T. Dirksen & Sheila Riazi & , 2022. "Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31088-8
    DOI: 10.1038/s41467-022-31088-8
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    References listed on IDEAS

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    1. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
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