Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm.
Dysregulation of calcium signals because of defects of the 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), specific forms of multi-minicore disease (MmD; MIM # 255320) and centronuclear myopathy (CNM). Experimental data have shown 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 depletion of Ca(2+) from SR stores. 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. The fourth class of mutations are unveiled by wild type allele silencing, and cause a decrease of mutant RyR1 channels expression on SR membranes. In this review, we discuss the classes of RYR1 mutations which have been associated with CCD, MmD and related neuromuscular phenotypes.
Treves
Susan
S
Dipartimento di Medicina Sperimentale e Diagnostica, Universita' di Ferrara, 44100 Ferrara, Italy.
Jungbluth
Heinz
H
Muntoni
Francesco
F
Zorzato
Francesco
F
D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D020512:Myopathy, Central Core / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D051140:Selenoproteins / Q000235:genetics
D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C435489:SELENON protein, human; D051140:Selenoproteins