Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA.
Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
Int J Mol Sci. 2024 Oct 19;25(20):11269. doi: 10.3390/ijms252011269.
Environmental heat stress represents a pervasive threat to warfighters, athletes, and occupational workers, impacting performance and increasing the risk of injury. Exertional heat illness (EHI) is a spectrum of clinical disorders of increasing severity. While frequently predictable, EHI can occur unexpectedly and may be followed by long-term comorbidities, including cardiovascular dysfunction and exercise intolerance. The objective of this study was to assess genetic factors contributing to EHI. Whole-exome sequencing was performed in a cohort of 53 cases diagnosed with EHI. Rare variants in prioritized gene sets were analyzed and classified per published guidelines. Clinically significant pathogenic and potentially pathogenic variants were identified in 30.2% of the study cohort. Variants were found in 14 genes, including the previously known and genes and 12 other genes (, , , , , and genes for mitochondrial disorders) reported here for the first time in EHI. Supporting structural and functional studies of the p.Arg905Trp variant show that it impairs the thermal sensitivity of the TRPM4 channel, revealing a potentially new molecular mechanism contributing to EHI susceptibility. Our study demonstrates associations between EHI and genes implicated in muscle disorders, cardiomyopathies, thermoregulation, and oxidative phosphorylation deficiencies. These results expand the genetic heterogeneity of EHI and shed light on its molecular pathogenesis.
环境热应激对作战人员、运动员和职业工人构成普遍威胁，影响表现并增加受伤风险。运动性热疾病（EHI）是一系列严重程度不断增加的临床疾病。虽然经常可以预测，但 EHI 可能会突然发生，并且可能会随之出现长期合并症，包括心血管功能障碍和运动不耐受。本研究的目的是评估导致 EHI 的遗传因素。对 53 例确诊为 EHI 的病例进行了全外显子组测序。根据已发表的指南分析和分类优先基因集中的罕见变异。在 30.2%的研究队列中发现了具有临床意义的致病性和潜在致病性变异。在 14 个基因中发现了变异，包括先前已知的 和 基因以及 12 个其他基因（ 、 、 、 、 、 和基因），这些基因以前在 EHI 中首次报道。支持对 p.Arg905Trp 变异体的结构和功能研究表明，它会损害 TRPM4 通道的热敏感性，揭示了导致 EHI 易感性的潜在新分子机制。我们的研究表明 EHI 与肌肉疾病、心肌病、体温调节和氧化磷酸化缺陷相关的基因之间存在关联。这些结果扩展了 EHI 的遗传异质性，并阐明了其分子发病机制。
