title: A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates.
abstract: A missense mutation in the calsequestrin-1 gene (CASQ1) was found in a group of patients with a myopathy characterized by weakness, fatigue, and the presence of large vacuoles containing characteristic inclusions resulting from the aggregation of sarcoplasmic reticulum (SR) proteins. The mutation affects a conserved aspartic acid in position 244 (p.Asp244Gly) located in one of the high-affinity Ca(2+) -binding sites of CASQ1 and alters the kinetics of Ca(2+) release in muscle fibers. Expression of the mutated CASQ1 protein in COS-7 cells showed a markedly reduced ability in forming elongated polymers, whereas both in cultured myotubes and in in vivo mouse fibers induced the formation of electron-dense SR vacuoles containing aggregates of the mutant CASQ1 protein that resemble those observed in muscle biopsies of patients. Altogether, these results support the view that a single missense mutation in the CASQ1 gene causes the formation of abnormal SR vacuoles containing aggregates of CASQ1, and other SR proteins, results in altered Ca(2+) release in skeletal muscle fibers, and, hence, is responsible for the clinical phenotype observed in these patients.
authors.affiliation: Molecular Medicine Section, Department of Molecular and Developmental Medicine, University of Siena and Azienda Ospedaliera Universitaria Senese, Siena, 53100, Italy; IIM, Interuniversity Institute of Myology.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rossi
authors.forename: Bianca
authors.initials: B
authors.lastname: Vezzani
authors.forename: Lucia
authors.initials: L
authors.lastname: Galli
authors.forename: Cecilia
authors.initials: C
authors.lastname: Paolini
authors.forename: Luana
authors.initials: L
authors.lastname: Toniolo
authors.forename: Enrico
authors.initials: E
authors.lastname: Pierantozzi
authors.forename: Simone
authors.initials: S
authors.lastname: Spinozzi
authors.forename: Virginia
authors.initials: V
authors.lastname: Barone
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
authors.forename: Luca
authors.initials: L
authors.lastname: Bello
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenacchi
authors.forename: Gaetano
authors.initials: G
authors.lastname: Vattemi
authors.forename: Giuliano
authors.initials: G
authors.lastname: Tomelleri
authors.forename: Giulia
authors.initials: G
authors.lastname: Ricci
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.forename: Feliciano
authors.initials: F
authors.lastname: Protasi
authors.forename: Carlo
authors.initials: C
authors.lastname: Reggiani
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Sorrentino
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002155:Calsequestrin; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000648:ultrastructure; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree; D066263:Protein Aggregation, Pathological / Q000235:genetics*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure; D055815:Young Adult
chemical_list: C503129:CASQ1 protein, human; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; D002118:Calcium
keywords: CASQ1; aggregate myopathy; calsequestrin; sarcoplasmic reticulum; skeletal muscle