Key result
CASQ1 missense mutation causes vacuolar myopathy by altering calcium release and inducing abnormal sarcoplasmic reticulum vacuoles.
Why the study?
Does the p.Asp244Gly mutation in the CASQ1 gene cause vacuolar myopathy and altered Ca(2+) release?
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.
May inform genetic evaluation of vacuolar myopathies; leaves open clinical validation before diagnostic adoption.
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.
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Rossi et al. (2014) studied 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.
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