A Calsequestrin-1 mutation associated with a skeletal muscle disease alters sarcoplasmic Ca2+ release

Maria Cristina D'Adamo, Luigi Sforna, Sergio Visentin, Alessandro Grottesi, Llenio Servettini, Luca Guglielmi, Lara Macchioni, Simona Saredi, Maurizio Curcio, Chiara De Nuccio, Sonia Hasan, Lanfranco Corazzi, Fabio Franciolini, Marina Mora, Luigi Catacuzzeno, Mauro Pessia

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


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".

Original languageEnglish
Article numbere0155516
JournalPLoS ONE
Issue number5
Publication statusPublished - May 2016
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • General


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