Variations in the TRPV1 gene are associated to exertional heat stroke

• Published in: Journal of science and medicine in sport Vol. 23; no. 11; pp. 1021 - 1027
• Main Authors: Bosson, Caroline, Rendu, John, Pelletier, Laurent, Abriat, Amandine, Chatagnon, Amandine, Brocard, Julie, Brocard, Jacques, Figarella-Branger, Dominique, Ducreux, Sylvie, van Coppenolle, Fabien, Sagui, Emmanuel, Marty, Isabelle, Roux-Buisson, Nathalie, Faure, Julien
• Format: Journal Article
• Language: English
• Published: Australia Elsevier Ltd 01-11-2020; Elsevier Limited; Elsevier
• Subjects: Adult; Body temperature; Consciousness; Disease; Fainting; Fever; Football; France; Genes; Genetic Predisposition to Disease; Heat; Heat exhaustion; Heat Stroke - genetics; Heatstroke; HEK293 Cells; Humans; Hyperthermia; In vitro contracture test; Life Sciences; Male; Malignant hyperthermia; Military Personnel; Multiple organ dysfunction syndrome; Musculoskeletal system; Mutagenesis; Mutation; Mutation, Missense; Pathophysiology; Patients; Software; Thermogenesis; TRPV Cation Channels - genetics; Whole exome sequencing; France; United States > US; Germany; Heat exhaustion; Thermogenesis; Malignant hyperthermia; In vitro contracture test; Whole exome sequencing
• ISSN: 1440-2440; 1878-1861
• DOI: 10.1016/j.jsams.2020.04.018

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
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.