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BJA Advance Access originally published online on April 3, 2009
British Journal of Anaesthesia 2009 102(5):642-649; doi:10.1093/bja/aep061
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© The Author [2009]. Published by Oxford University Press on behalf of The Board of Directors of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournal.org

Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases

M. Broman1,*, A. Gehrig2, G. Islander1, M. Bodelsson1, E. Ranklev-Twetman1, H. Rüffert3 and C. R. Müller2

1 Department of Anaesthesiology and Intensive Care, Lund University Hospital, S-22185 Lund, Sweden
2 Department of Human Genetics, Biocentre, University of Würzburg, Germany
3 Department of Anaesthesiology and Intensive Care, Leipzig University Hospital, Germany

* Corresponding author. E-mail: marcus.broman{at}skane.se

Background: Malignant hyperthermia (MH), linked to the ryanodine receptor 1 gene (RYR1) on chromosome 19, is a potentially lethal pharmacogenetic disorder which may lead to a disturbance of intracellular calcium homeostasis when susceptible individuals are exposed to halogenated anaesthetics, suxamethonium, or both. Central core disease (CCD) is a rare dominantly inherited congenital myopathy allelic to MH-susceptibility.

Methods: In this study, 14 unrelated MH-susceptible probands and one CCD patient from Sweden were screened for mutations in the RYR1. Since the RYR1 is also expressed in B-lymphocytes, RYR1-cDNA was transcribed from total RNA extracted from white blood cells.

Results: We detected two known RYR1 mutations and two previously described unclassified sequence variants. In addition, six novel sequence variants were detected. All mutations or sequence variants were verified on genomic DNA. Seven of the probands did not show any candidate mutation, although the total coding region of RYR1 was sequenced. Segregation data in in vitro contracture tested family members of three probands support a causative role of three of the novel sequence variants.

Conclusions: Our study contributes to the genetic aetiology of MH in Sweden, but also raises questions about the involvement of genes other than RYR1 since nearly half of the probands did not show any sequence variants in the total coding region of the RYR1.

Keywords: anaesthesia, general; complications, malignant hyperthermia; genetic factors; safety


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