Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept

Abstract

This article reviews advancements in the genetics of malignant hyperthermia, new technologies and approaches for its diagnosis, and the existing limitations of genetic testing for malignant hyperthermia. It also reviews the various RYR1-related disorders and phenotypes, such as myopathies, exertional rhabdomyolysis, and bleeding disorders, and examines the connection between these disorders and malignant hyperthermia.

Figure-1

A. A schematic illustration of the N-terminal domains docked in the pseudo-atomic model of the RyR1 tetramer. The RyR1 N-terminal domain (NTD), corresponding to the MH hot spot 1, is composed of three subdomains: A, B, and C. Interactions among the domains A, B, and C on the same RyR1 subunit together with the interactions between domains of the neighboring subunits are involved in the global conformational RyR1 transmissions that control effector-induced channel gating. The variants impair the domain-domain interactions and thus would cause the RyR1 channel dysfunction. B. A schematic model of domain organization in a RyR1 monomer, composed of the N-terminal domain (NTD), the central domain and the channel domain. Each domain consists of several interconnected subdomains. The channel domain consists of the six transmembrane fragments (S1-S6), and pore helices with the selectivity filter (SF), the linker helix of S4-S5, the voltage sensor like domain (VSL), and C-terminal domain (CTD). Binding Ca²⁺ to the central domain, initiates a cascade of conformational transmissions via allosteric intradomain and interdomain interactions from the central domain to the NTD, to the VSL, the CTD and S6, ultimately inducing opening of the channel. Together with the amino acids forming the ion channel – the pore helix and the selectivity filter (amino acid 4894-4900), the S4-S5 linker (amino acid 4830-4841), Gly4934 – which serves as a “hinge” for the outward movement of the helix S6, and the CTD (amino acid 4957-5033) are all critical for RyR1 channel gating (modified with permission from reference 64).