Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia

Journal of Neuromuscular Diseases
Remai ParkerKathryn M Stowell

Abstract

Central core disease and malignant hyperthermia are human disorders of skeletal muscle resulting from aberrant Ca2+ handling. Most malignant hyperthermia and central core disease cases are associated with amino acid changes in the type 1 ryanodine receptor (RyR1), the skeletal muscle Ca2+-release channel. Malignant hyperthermia exhibits a gain-of-function phenotype, and central core disease results from loss of channel function. For a variant to be classified as pathogenic, functional studies must demonstrate a correlation with the pathophysiology of malignant hyperthermia or central core disease. We assessed the pathogenicity of four C-terminal variants of the ryanodine receptor using functional analysis. The variants were identified in families affected by either malignant hyperthermia or central core disease. Four variants were introduced separately into human cDNA encoding the skeletal muscle ryanodine receptor. Following transient expression in HEK-293T cells, functional studies were carried out using calcium release assays in response to an agonist. Two previously characterized variants and wild-type skeletal muscle ryanodine receptor were used as controls. The p.Met4640Ile variant associated with central core disease sho...Continue Reading

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Citations

Dec 26, 2019·Disease Models & Mechanisms·Aurora FustoElena Pegoraro
Aug 30, 2018·Journal of Neurology·Joshua J ToddKatherine G Meilleur

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Methods Mentioned

BETA
biopsy
biopsies
reverse-transcription PCR
PCR
transfection
Protein Assay
electrophoresis
X-ray
exome sequencing

Software Mentioned

ExAc
OriginLab Origin

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