CACNA2D4 variants are associated with exertional heat stroke susceptibility

Exertional Heat Stroke (EHS) is a life-threatening disease defined by severe hyperthermia, with a body temperature above 40{degrees}C, associated with a sudden neurological dysfunction, observed in healthy individuals exposed to intensive physical exercise. EHS shares many clinical and biological similarities with Malignant Hyperthermia (MH), a pharmacogenetic disorder associated with mutations in the RYR1, CACNA1S and STAC3 genes involved in calcium release required for skeletal muscle contraction. Several pieces of evidence support the existence of inherited genetic mutations that predispose some patients to EHS, but to date, the genetic bases of EHS remain poorly documented. Whole Exome Sequencing on a cohort of soldiers presenting with an EHS episode led to the identification of variants in the CACNA2D4 gene, encoding the 2{delta}4 isoform of regulatory subunits of voltage-gated calcium channels. In vitro expression of these variants suggested they can affect the function of the protein, and modulate the properties of the Cav1.1 channel. A mouse model with a knock-in for the S299R variant showed EHS-like crisis with signs of rhabdomyolysis and an elevation in core body temperature when submitted to an intense exercise protocol. We show that a CACNA2D4 transcript is expressed in mouse skeletal muscle and that the presence of the S299R variant in 2{delta}4 induces a modification in the calcium flux triggered by muscle cells depolarization. Altogether, our data point to the involvement of the CACNA2D4 gene in skeletal muscle function and suggest that its genetic variants could be responsible for EHS susceptibility.