A Calsequestrin-1 Mutation Associated with a Skeletal Muscle Disease Alters Sarcoplasmic Ca2+ Release

Abstract

An autosomal dominant protein aggregate myopathy, characterized by high plasma creatine kinase and calsequestrin-1 (CASQ1) accumulation in skeletal muscle, has been recently associated with a missense mutation in CASQ1 gene. The mutation replaces an evolutionarily-conserved aspartic acid with glycine at position 244 (p.D244G) of CASQ1, the main sarcoplasmic reticulum (SR) Ca2+ binding and storage protein localized at the terminal cisternae of skeletal muscle cells. Here, immunocytochemical analysis of myotubes, differentiated from muscle-derived primary myoblasts, shows that sarcoplasmic vacuolar aggregations positive for CASQ1 are significantly larger in CASQ1-mutated cells than control cells. A strong co-immuno staining of both RyR1 and CASQ1 was also noted in the vacuoles of myotubes and muscle biopsies derived from patients. Electrophysiological recordings and sarcoplasmic Ca2+ measurements provide evidence for less Ca2+ release from the SR of mutated myotubes when compared to that of controls. These findings further clarify the pathogenic nature of the p.D244G variant and point out defects in sarcoplasmic Ca2+ homeostasis as a mechanism underlying this human disease, which could be distinctly classified as “CASQ1-couplonopathy”.

A comparison of prenatal muscle transcriptome and proteome profiles between pigs with divergent growth phenotypes

“…CASQ1 mediates skeletal muscle development and contraction . CRYAB has negative regulation of cell growth and organ development .…”

Calsequestrin: a well-known but curious protein in skeletal muscle

“…D244G (a heterozygous missense mutation in the CASQ1 gene) was the first identified CASQ1 mutant in patients showing mild myopathy characterized by muscle weakness, fatigue, and the presence of large vacuoles [165][166][167] . D244G induces misfolding and abnormal aggregation of CASQ1 (which is different from the physiological CASQ1 polymers) due to the loss of the electric charge in D244 that is involved in the Ca 2+ -binding and Ca 2+ -dependent polymerization of CASQ1.…”

CASQ1‐related myopathy: The first report from China and the literature review

“…In 2014, Rossi et al 5 reported the first CASQ1 mutation, c.731A > G (p.Asp244Gly) in eight patients characterized by mild proximal weakness, fatigue, and large vacuoles containing aggregation of SR proteins. Subsequently, Lewis et al, 10 D'Adamo et al 11 and Semplicini et al 9 identified the similar phenotype in patients with c.731A > G (p.Asp244Gly). In these patients, sarcoplasmic vacuolar aggregations and reduced Ca 2+ release from the SR induced by abnormal CASQ1 aggregates were observed.…”