Functional properties of RYR1 mutations identified in Swedish patients with malignant hyperthermia and central core disease

Vukcevic, Mirko and Broman, Marcus and Islander, Gunilla and Bodelsson, Mikael and Ranklev-Twetman, Eva and Müller-Reible, Clemens and Treves, Susan. (2010) Functional properties of RYR1 mutations identified in Swedish patients with malignant hyperthermia and central core disease. Anesthesia and Analgesia, 111 (1). pp. 185-190.

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Official URL: http://edoc.unibas.ch/dok/A6174329

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BACKGROUND: A diagnosis of malignant hyperthermia susceptibility by in vitro contraction testing can often only be performed at specialized laboratories far away from where patients live. Therefore, we have designed a protocol for genetic screening of the RYR1-cDNA and for functional testing of newly identified ryanodine receptor 1 (RYR1) gene variants in B lymphocytes isolated from peripheral blood samples drawn at local primary care centers.
METHODS: B lymphocytes were isolated for the extraction of RYR1-mRNA and genomic DNA and for establishment of lymphoblastoid B cell lines in 5 patients carrying yet unclassified mutations in the RYR1. The B lymphoblastoid cell lines were used to study resting cytoplasmic calcium concentration, the peak calcium transient induced by the sarco(endo)plasmic reticulum Ca-ATPase inhibitor thapsigargin, and the dose-dependent calcium release induced by the ryanodine receptor agonist 4-chloro-m-cresol.
RESULTS: It was possible to extract mRNA for cDNA synthesis and to create B lymphocyte clones from all samples. All B lymphoblastoid cell lines carrying RYR1 candidate mutations showed significantly increased resting cytoplasmic calcium levels as well as a shift to lower concentrations of 4-chloro-m-cresol inducing calcium release compared with controls.
CONCLUSIONS: Peripheral blood samples are stable regarding RNA and DNA extraction and establishment of lymphoblastoid B cell lines after transportation at ambient temperature over large distances by ordinary mail. Functional tests on B cells harboring the newly identified amino acid substitutions indicate that they alter intracellular Ca2+ homeostasis and are most likely causative of malignant hyperthermia.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Perioperative Patient Safety (Girard/Treves)
UniBasel Contributors:Treves, Susan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Lippincott, Williams & Wilkins
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:31 May 2017 09:59
Deposited On:25 Oct 2013 08:33

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