Communicated by Jürgen Horst
JP-45/JSRP1 Variants Affect Skeletal Muscle Excitation–Contraction Coupling by Decreasing the Sensitivity of the Dihydropyridine Receptor
Article first published online: 11 OCT 2012
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 1, pages 184–190, January 2013
How to Cite
Yasuda, T., Delbono, O., Wang, Z.-M., Messi, M. L., Girard, T., Urwyler, A., Treves, S. and Zorzato, F. (2013), JP-45/JSRP1 Variants Affect Skeletal Muscle Excitation–Contraction Coupling by Decreasing the Sensitivity of the Dihydropyridine Receptor. Hum. Mutat., 34: 184–190. doi: 10.1002/humu.22209
Contract grant sponsors: Department of Anesthesia, Basel University Hospital; Swiss National Science Foundation (SNF 310030-129785); Association Française contre les Myopathies (AFM); National Institutes of Health (grants AG13934 and AG15820); Japan Society for the Promotion of Science (No. 23592291); Wake Forest University Pepper Older Americans Independence Center (P30-AG21332).
- Issue published online: 20 DEC 2012
- Article first published online: 11 OCT 2012
- Accepted manuscript online: 24 AUG 2012 09:48AM EST
- Manuscript Accepted: 14 AUG 2012
- Manuscript Received: 22 MAY 2012
- Department of Anesthesia
- Basel University Hospital
- Swiss National Science Foundation. Grant Number: SNF 310030-129785
- Association Française contre les Myopathies (AFM)
- National Institutes of Health. Grant Numbers: AG13934, AG15820
- Japan Society for the Promotion of Science. Grant Number: 23592291
- Wake Forest University Pepper Older Americans Independence Center. Grant Number: P30-AG21332
- dihydropyridine receptor;
- skeletal muscle
JP-45 (also JP45; encoded by JSRP1) is an integral protein constituent of the skeletal muscle sarcoplasmic reticulum junctional face membrane interacting with Cav1.1 (the α.1 subunit of the voltage-sensing dihydropyridine receptor, DHPR) and the luminal calcium-binding protein calsequestrin. Two JSRP1 variants have been found in the human population: c.323C>T (p.P108L) in exon 5 and c.449G>C (p.G150A) in exon 6, but nothing is known concerning the incidence of these polymorphisms in the general population or in patients with neuromuscular diseases nor the impact of the polymorphisms on excitation–contraction (EC) coupling. In the present report, we investigated the frequencies of these two JSRP1 polymorphisms in the Swiss malignant hyperthermia population and studied the functional impact of the variants on EC coupling. Our results show that the polymorphisms are equally distributed among malignant hyperthermia negative, malignant hyperthermia equivocal, and malignant hyperthermia susceptible individuals. Interestingly, however, the presence of either one of these JP-45 variants decreased the sensitivity of the DHPR to activation. The presence of a JSRP1 variant may explain the variable phenotype seen in patients with malignant hyperthermia carrying the same mutation and, more importantly, may counteract the hypersensitivity of EC coupling caused by mutations in the RYR1 gene.