Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Physiology, University of Rochester, Rochester, NY, USA.
Nat Commun. 2022 Jun 13;13(1):3403. doi: 10.1038/s41467-022-31088-8.
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.
运动性热病（EHI）和恶性高热（MH）是与肌肉分解相关的危及生命的病症，其发生与挥发性麻醉剂、运动和高温等触发因素有关。为了鉴定导致 EHI 和/或 MH 的新的遗传变异，我们对 EHI/MH 和/或异常咖啡因-氟烷收缩试验的队列进行了基因组测序。在五个人中，我们发现了编码衔接蛋白 junctin 的 ASPH 基因中的罕见致病性杂合变异，该蛋白是兴奋-收缩偶联的调节剂。我们使用正交的临床前模型、CRISPR 编辑的 C2C12 肌管和转基因斑马鱼来验证这些变异的致病性。总的来说，我们证明了 ASH 变异是 EHI 和 MH 易感性的一个新原因。
