Variants in ASPH Cause Exertional Heat Illness and Are Associated With Malignant Hyperthermia Susceptibility

Authors

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
James J Dowling

Publication Date

6-13-2022

Journal

Nature Communications

DOI

10.1038/s41467-022-31088-8

PMID

35697689

PMCID

PMC9192596

PubMedCentral® Posted Date

6-13-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Caffeine, Calcium-Binding Proteins, Heat Stress Disorders, Humans, Malignant Hyperthermia, Membrane Proteins, Mixed Function Oxygenases, Muscle Contraction, Muscle Fibers, Skeletal, Muscle Proteins, Zebrafish

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.

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