Faure, J. | Search bioRxiv

bioRxiv2026

CACNA2D4 variants are associated with exertional heat stroke susceptibility

Exertional Heat Stroke (EHS) is a life-threatening disease defined by severe hyperthermia and sudden neurological dysfunction in healthy individuals exposed to intense physical exercise. As is the case with some forms of malignant hyperthermia, mutations in genes involved in skeletal muscle contraction could predispose some patients to EHS. However, the genetic basis of EHS remains poorly documented. Here we identify EHS-associated variants in the CACNA2D4 gene encoding the Cav Ca2+ channel subunit, 2{delta}4, and describe their impact in heterologous expression systems and a knock-in mutant mouse strain heterozygous for the S299R variant (S299R+/-). In transfected cells, each CACNA2D4 variant, including S299R, affected the trafficking and function of 2{delta}4 and its regulation of the Cav1.1 channel. S299R+/-mice 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 cell depolarization. Altogether, our data reveal an unexpected connection between CACNA2D4 gene variants and pathophysiological alterations in skeletal muscle Ca2+ signaling that may increase EHS susceptibility.

genetics↗

bioRxiv2020

Mutations in MYLPF cause a novel segmental amyoplasia that manifests as distal arthrogryposis

We identified ten persons in six consanguineous families with Distal Arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T, p.(Cys157Phe) or c.469T>C, p.(Cys157Arg)) affecting the same residue of myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A, p.(Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly-inherited DA, a c.98C>T, p.(Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.

genetics↗