Format

Send to

Choose Destination
Hum Mutat. 2014 Oct;35(10):1163-70. doi: 10.1002/humu.22631. Epub 2014 Sep 10.

A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates.

Author information

1
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.

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.

KEYWORDS:

CASQ1; aggregate myopathy; calsequestrin; sarcoplasmic reticulum; skeletal muscle

PMID:
25116801
PMCID:
PMC4177304
DOI:
10.1002/humu.22631
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center