CHU Grenoble Alpes IBP, Génétique Moléculaire : Maladies Héréditaires et Oncologie, France; Grenoble Institute of Neurosciences, Inserm U1216, Cellular Myology and Pathology, Grenoble Alpes, University, Grenoble, France.
Grenoble Institute of Neurosciences, Inserm U1216, Cellular Myology and Pathology, Grenoble Alpes, University, Grenoble, France.
J Sci Med Sport. 2020 Nov;23(11):1021-1027. doi: 10.1016/j.jsams.2020.04.018. Epub 2020 May 18.
Exertional Heat Stroke (EHS) is one of the top three causes of sudden death in athletes. Extrinsic and intrinsic risk factors have been identified but the genetic causes still remain unclear. Our aim was to identify genes responsible for EHS, which is a necessary step to identify patients at risk and prevent crises.
Genetic and functional laboratory studies METHODS: Whole Exome Sequencing (WES) was performed to search for candidate genes in a cohort of 15 soldiers who had a documented EHS episode. In silico and in vitro functional studies were performed to evaluate the effect of mutations identified in the candidate gene TRPV1.
WES led to the identification of two missense variations in the TRPV1 gene. These variations were very rare or unreported in control databases and located in critical domains of the protein. In vitro functional studies revealed that both variations induce a strong modification of the channel response to one of its natural agonist, the capsaicin.
We evidenced mutations altering channel properties of the TRPV1 gene and demonstrated that TRPV1, which is involved in thermoregulation and nociception, is a new candidate gene for EHS. Our data provide the bases to explore genetic causes and molecular mechanisms governing the pathophysiology of EHS.
运动性热射病（EHS）是运动员猝死的三大原因之一。已经确定了外在和内在的危险因素，但遗传原因仍不清楚。我们的目的是确定导致 EHS 的基因，这是识别高危患者和预防危机的必要步骤。
遗传和功能实验室研究
对 15 名有明确 EHS 病史的士兵进行全外显子组测序（WES），以寻找候选基因。进行了计算机模拟和体外功能研究，以评估在候选基因 TRPV1 中发现的突变的影响。
WES 导致 TRPV1 基因中发现了两个错义变异。这些变异在对照数据库中非常罕见或未报告，位于蛋白质的关键结构域。体外功能研究表明，这两种变异都强烈改变了通道对其天然激动剂之一辣椒素的反应。
我们证明了改变 TRPV1 基因通道特性的突变，并证明 TRPV1 参与体温调节和痛觉，是 EHS 的一个新候选基因。我们的数据为探索 EHS 病理生理学的遗传原因和分子机制提供了基础。
