title: 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".
authors.affiliation: Section of Physiology & Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: D'Adamo
authors.affiliation: Section of Physiology & Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Sforna
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Visentin
authors.affiliation: SuperComputing Applications and Innovation-CINECA, Roma, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Grottesi
authors.affiliation: Section of Physiology & Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.
authors.forename: Llenio
authors.initials: L
authors.lastname: Servettini
authors.affiliation: Section of Physiology & Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Guglielmi
authors.affiliation: Section of Physiology & Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Macchioni
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Saredi
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Curcio
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: De Nuccio
authors.affiliation: Section of Physiology & Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Hasan
authors.affiliation: Section of Physiology & Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.
authors.forename: Lanfranco
authors.initials: L
authors.lastname: Corazzi
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Franciolini
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Catacuzzeno
authors.affiliation: Section of Physiology & Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.|Department of Physiology & Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pessia
mesh_terms: D000200:Action Potentials; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002155:Calsequestrin; D004594:Electrophysiology; D006706:Homeostasis; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics*; D008958:Models, Molecular; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009135:Muscular Diseases / Q000378:metabolism*; D009154:Mutation; D020125:Mutation, Missense; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: C503129:CASQ1 protein, human; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D024101:Mitochondrial Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D002118:Calcium