Dysregulation of calcium signals due to defects of skeletal muscle sarcoplasmic reticulum calcium release channel (ryanodine receptor; RyR1) is causative of several congenital muscle disorders including malignant hyperthermia (MH; MIM #145600), Central Core Disease (CCD; MIM #11700), Multiminicore Disease (MmD; MIM # 255320) and Centronuclear myopathy (CNM). Experimental data have show that RYR1 mutations result mainly in four types of channel defects. One class of RYR1 mutations (MH) cause the channels to become hypersensitive to activation by electrical and pharmacological stimuli. The second class of RYR1 mutations (CCD) result in leaky channels leading to a depletion of Ca2+ from the SR store. A third class of RYR1 mutations linked to CCD causes excitation-contraction uncoupling, whereby activation of the voltage sensor Cav1.1 is unable to release calcium from the SR store. The forth class of mutations are unveiled by wild type allele silencing, and cause a decrease of mutant RyR1 channels to be expressed in SR membranes. In this review, we discuss the classes of RYR1 mutations which have been associated with CCD, MmD and related neuromuscular phenotypes.
Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm.
TREVES, Susan Nella;ZORZATO, Francesco
2009
Abstract
Dysregulation of calcium signals due to defects of skeletal muscle sarcoplasmic reticulum calcium release channel (ryanodine receptor; RyR1) is causative of several congenital muscle disorders including malignant hyperthermia (MH; MIM #145600), Central Core Disease (CCD; MIM #11700), Multiminicore Disease (MmD; MIM # 255320) and Centronuclear myopathy (CNM). Experimental data have show that RYR1 mutations result mainly in four types of channel defects. One class of RYR1 mutations (MH) cause the channels to become hypersensitive to activation by electrical and pharmacological stimuli. The second class of RYR1 mutations (CCD) result in leaky channels leading to a depletion of Ca2+ from the SR store. A third class of RYR1 mutations linked to CCD causes excitation-contraction uncoupling, whereby activation of the voltage sensor Cav1.1 is unable to release calcium from the SR store. The forth class of mutations are unveiled by wild type allele silencing, and cause a decrease of mutant RyR1 channels to be expressed in SR membranes. In this review, we discuss the classes of RYR1 mutations which have been associated with CCD, MmD and related neuromuscular phenotypes.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
