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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • COS Cells
  • Calcium / metabolism
  • Calcium-Binding Proteins / chemistry
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism
  • Chlorocebus aethiops
  • Female
  • Humans
  • Lysosomal Storage Diseases / genetics
  • Lysosomal Storage Diseases / metabolism*
  • Lysosomal Storage Diseases / pathology
  • Male
  • Mice
  • Middle Aged
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Muscle Fibers, Skeletal / ultrastructure
  • Muscular Diseases / genetics
  • Muscular Diseases / metabolism*
  • Muscular Diseases / pathology
  • Mutation, Missense*
  • Pedigree
  • Protein Aggregation, Pathological / genetics*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sarcoplasmic Reticulum / metabolism
  • Sarcoplasmic Reticulum / ultrastructure
  • Vacuoles / metabolism
  • Vacuoles / ultrastructure
  • Young Adult

Substances

  • CASQ1 protein, human
  • Calcium-Binding Proteins
  • Mitochondrial Proteins
  • Recombinant Proteins
  • Calcium

Supplementary concepts

  • Vacuolar myopathy