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dc.contributor.authorParker, R
dc.contributor.authorSchiemann, AH
dc.contributor.authorLangton, E
dc.contributor.authorBulger, T
dc.contributor.authorPollock, N
dc.contributor.authorBjorksten, A
dc.contributor.authorGillies, R
dc.contributor.authorHutchinson, D
dc.contributor.authorRoxburgh, R
dc.contributor.authorStowell, KM
dc.date.accessioned2020-12-21T04:29:35Z
dc.date.available2020-12-21T04:29:35Z
dc.date.issued2017
dc.identifierpii: JND170210
dc.identifier.citationParker, 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.
dc.identifier.issn2214-3599
dc.identifier.urihttp://hdl.handle.net/11343/257646
dc.description.abstractBACKGROUND: 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.
dc.languageeng
dc.publisherIOS Press
dc.titleFunctional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia.
dc.typeJournal Article
dc.identifier.doi10.3233/JND-170210
melbourne.affiliation.departmentPharmacology and Therapeutics
melbourne.source.titleJournal of Neuromuscular Diseases
melbourne.source.volume4
melbourne.source.issue2
melbourne.source.pages147-158
dc.rights.licenseCC BY-NC
melbourne.elementsid1285237
melbourne.openaccess.pmchttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467713
melbourne.contributor.authorBjorksten, Andrew
dc.identifier.eissn2214-3602
melbourne.accessrightsOpen Access


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