Intracellular calcium leak as a therapeutic target for RYR1-related myopathies

Alexander Kushnir, Joshua J. Todd, Jessica W. Witherspoon, Qi Yuan, Steven Reiken, Harvey Lin, Ross H. Munce, Benjamin Wajsberg, Zephan Melville, Oliver B. Clarke, Kaylee Wedderburn-Pugh, Anetta Wronska, Muslima S. Razaqyar, Irene C. Chrismer, Monique O. Shelton, Ami Mankodi, Christopher Grunseich, Mark A. Tarnopolsky, Kurenai Tanji, Michio HiranoSheila Riazi, Natalia Kraeva, Nicol C. Voermans, Angela Gruber, Carolyn Allen, Katherine G. Meilleur, Andrew R. Marks

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1-related myopathies (RYR1-RM), a broad spectrum of rare neuromuscular disorders. We sought to determine whether RYR1-RM affected individuals exhibit pathologic, leaky RyR1 and whether variant location in the channel structure can predict pathogenicity. Skeletal muscle biopsies were obtained from 17 individuals with RYR1-RM. Mutant RyR1 from these individuals exhibited pathologic SR calcium leak and increased activity of calcium-activated proteases. The increased calcium leak and protease activity were normalized by ex-vivo treatment with S107, a RyR stabilizing Rycal molecule. Using the cryo-EM structure of RyR1 and a new dataset of > 2200 suspected RYR1-RM affected individuals we developed a method for assigning pathogenicity probabilities to RYR1 variants based on 3D co-localization of known pathogenic variants. This study provides the rationale for a clinical trial testing Rycals in RYR1-RM affected individuals and introduces a predictive tool for investigating the pathogenicity of RYR1 variants of uncertain significance.

Original languageEnglish (US)
Pages (from-to)1089-1104
Number of pages16
JournalActa neuropathologica
Issue number6
StatePublished - Jun 1 2020
Externally publishedYes


  • Calcium
  • Central core disease
  • Genetics
  • RyR1-related myopathy
  • Ryanodine receptor
  • Therapeutics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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