A Mutation in the CASQ1 Gene Causes a Vacuolar Myopathy with Accumulation of Sarcoplasmic Reticulum Protein Aggregates

作者：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^*

来源：Human Mutation, 2014, 35(10): 1163-1170.

DOI：10.1002/humu.22631

• aggregate myoPathy
• CASQl
• casequestrin
• sarcoplasmic reticulum
• skeletal muscle

A missense mutation in the calseques r n 1 gene (CASQ1) was found in a group of patients with a mypathy characterized by Mfeakness, fa igue, and the pres ence of large vacuoles containing characteristic inclusion suiting from the aggregation of sarcoplasmic reticulum (SR) proteins. The mutation affects a conserved asparc acid in position 244 (p.Asp24=1Gly) located in one of he high-affinity Ca -binding sites of CASQ1 and alters he kinetics of Ca :2+ release in muscle fibers. Expression of the mutated CASQ1 protein in COS-7 cells showed a arkedly 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 pa, ents. 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%26apos;+ lease in skeletal muscle fibers, and, hence, is responsible or the clinical phenotype observed in these patients.

• 出版日期2014-10