A missense mutation (p.Asp244Gly) in the CASQ1 gene causes a vacuolar myopathy by altering Ca(2+) release and inducing the formation of abnormal sarcoplasmic reticulum vacuoles with protein aggregates.
Does the p.Asp244Gly mutation in the CASQ1 gene cause vacuolar myopathy and altered Ca(2+) release?
The p.Asp244Gly missense mutation in the CASQ1 gene is responsible for a specific vacuolar myopathy by causing SR protein aggregation and altered calcium release in skeletal muscle.
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.
Rossi et al. (Wed,) conducted a other in Vacuolar myopathy. CASQ1 gene mutation (p.Asp244Gly) was evaluated on Identification of genetic cause and functional characterization of the mutation. A missense mutation (p.Asp244Gly) in the CASQ1 gene causes a vacuolar myopathy by altering Ca(2+) release and inducing the formation of abnormal sarcoplasmic reticulum vacuoles with protein aggregates.