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

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    Author
    Parker, R; Schiemann, AH; Langton, E; Bulger, T; Pollock, N; Bjorksten, A; Gillies, R; Hutchinson, D; Roxburgh, R; Stowell, KM
    Date
    2017
    Source Title
    Journal of Neuromuscular Diseases
    Publisher
    IOS Press
    University of Melbourne Author/s
    Bjorksten, Andrew
    Affiliation
    Pharmacology and Therapeutics
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Parker, R., Schiemann, A. H., Langton, E., Bulger, T., Pollock, N., Bjorksten, A., Gillies, R., Hutchinson, D., Roxburgh, R. & Stowell, K. M. (2017). Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia.. J Neuromuscul Dis, 4 (2), pp.147-158. https://doi.org/10.3233/JND-170210.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257646
    DOI
    10.3233/JND-170210
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467713
    Abstract
    BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: The p.Met4640Ile variant associated with central core disease showed no difference in calcium release compared to wild-type. The p.Val4849Ile variant associated with malignant hyperthermia was more sensitive to agonist than wild-type but did not reach statistical significance and two variants (p.Phe4857Ser and p.Asp4918Asn) associated with central core disease were completely inactive. CONCLUSIONS: The p.Val4849Ile variant should be considered a risk factor for malignant hyperthermia, while the p.Phe4857Ser and p.Asp4918Asn variants should be classified as pathogenic for central core disease.

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