PUBLICATION
Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility
- Authors
- Endo, Y., Groom, L., Celik, A., Kraeva, N., Lee, C.S., Jung, S.Y., Gardner, L., Shaw, M.A., Hamilton, S.L., Hopkins, P.M., Dirksen, R.T., Riazi, S., Dowling, J.J.
- ID
- ZDB-PUB-220615-1
- Date
- 2022
- Source
- Nature communications 13: 3403 (Journal)
- Registered Authors
- Dowling, Jim
- Keywords
- none
- MeSH Terms
-
- Animals
- Caffeine/pharmacology
- Calcium-Binding Proteins
- Heat Stress Disorders*
- Humans
- Malignant Hyperthermia*/genetics
- Membrane Proteins
- Mixed Function Oxygenases
- Muscle Contraction
- Muscle Fibers, Skeletal
- Muscle Proteins
- Zebrafish/genetics
- PubMed
- 35697689 Full text @ Nat. Commun.
Citation
Endo, Y., Groom, L., Celik, A., Kraeva, N., Lee, C.S., Jung, S.Y., Gardner, L., Shaw, M.A., Hamilton, S.L., Hopkins, P.M., Dirksen, R.T., Riazi, S., Dowling, J.J. (2022) Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility. Nature communications. 13:3403.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping