Caroline Bosson1, John Rendu1, Laurent Pelletier2, Amandine Abriat3, Amandine Chatagnon4, Julie Brocard2, Jacques Brocard2, Dominique Figarella-Branger5, Sylvie Ducreux6, Fabien van Coppenolle6, Emmanuel Sagui7, Isabelle Marty2, Nathalie Roux-Buisson8, Julien Faure1. 1. 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. 2. Grenoble Institute of Neurosciences, Inserm U1216, Cellular Myology and Pathology, Grenoble Alpes, University, Grenoble, France. 3. Military Hospital Laveran, Service of Neurology, Marseille, France. 4. CHU Grenoble Alpes IBP, Génétique Moléculaire : Maladies Héréditaires et Oncologie, France. 5. Aix-Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, Hôpital de la Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France; Univ Aix-Marseille I, France. 6. Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA, Lyon, Université Claude Bernard, Bron, France. 7. European Hospital of Marseille, Marseille, France. 8. 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. Electronic address: nrouxbuisson@chu-grenoble.fr.
Abstract
OBJECTIVES: 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. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVES: 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. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Abderrezak Bouchama; Bisher Abuyassin; Cynthia Lehe; Orlando Laitano; Ollie Jay; Francis G O'Connor; Lisa R Leon Journal: Nat Rev Dis Primers Date: 2022-02-03 Impact factor: 52.329