Premium
A Mutation in the CASQ 1 Gene Causes a Vacuolar Myopathy with Accumulation of Sarcoplasmic Reticulum Protein Aggregates
Author(s) -
Rossi Daniela,
Vezzani Bianca,
Galli Lucia,
Paolini Cecilia,
Toniolo Luana,
Pierantozzi Enrico,
Spinozzi Simone,
Barone Virginia,
Pegoraro Elena,
Bello Luca,
Cenacchi Giovanna,
Vattemi Gaetano,
Tomelleri Giuliano,
Ricci Giulia,
Siciliano Gabriele,
Protasi Feliciano,
Reggiani Carlo,
Sorrentino Vincenzo
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22631
Subject(s) - biology , missense mutation , calsequestrin , myopathy , endoplasmic reticulum , vacuole , mutant , mutation , microbiology and biotechnology , biochemistry , gene , genetics , cytoplasm , ryanodine receptor
A missense mutation in the calsequestrin‐1 gene ( CASQ 1 ) 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. A sp244 G ly) located in one of the high‐affinity C a 2+ ‐binding sites of CASQ 1 and alters the kinetics of C a 2+ release in muscle fibers. Expression of the mutated CASQ 1 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 CASQ 1 protein that resemble those observed in muscle biopsies of patients. Altogether, these results support the view that a single missense mutation in the CASQ 1 gene causes the formation of abnormal SR vacuoles containing aggregates of CASQ 1, and other SR proteins, results in altered C a 2+ release in skeletal muscle fibers, and, hence, is responsible for the clinical phenotype observed in these patients.