Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility.
Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility.
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DOI：
10.1038/s41467-022-31088-8
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发表时间：
2022-06-13
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
中暑（EHI）和恶性高热（MH）是威胁生命的疾病，在包括挥发性麻醉剂、运动和高环境温度在内的触发因素的背景下与肌肉分解相关。为了鉴定易患EHI和/或MH的新的遗传变异，我们对EHI/MH和/或异常咖啡因-氟烷挛缩试验的队列进行了基因组测序。在五个人中，我们发现了罕见的，致病性杂合变异ASPH，一个基因编码连接蛋白，兴奋-收缩耦合的调节器。我们使用正交临床前模型、CRISPR编辑的C2 C12肌管和转基因斑马鱼验证了这些变体的致病性。总之，我们证明ASPH变异体代表了EHI和MH易感性的新原因。在大约30%的病例中，恶性高热和劳力性热病的遗传原因尚不清楚。为了解决这一障碍，作者对大量病例进行了基因组测序，鉴定了ASPH（一种编码连接蛋白的基因）的罕见变异，并在动物和细胞模型中验证了它们。
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. The genetic cause(s) of malignant hyperthermia and exertional heat illness are unknown in approximately 30% of cases. To address this barrier, the authors performed genome sequencing on a large cohort of cases, identifying rare variants in ASPH, a gene encoding junctin, and validating them in animal and cell models.
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