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Open Access Research article

The role of CACNA1S in predisposition to malignant hyperthermia

Danielle Carpenter1*, Christopher Ringrose1, Vincenzo Leo1, Andrew Morris2, Rachel L Robinson1, P Jane Halsall1, Philip M Hopkins1 and Marie-Anne Shaw3

Author Affiliations

1 MH Investigation Unit, Academic Unit of Anaesthesia, St James's University Hospital, Leeds, LS9 7TF, UK

2 Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK

3 Institute of Integrative and Comparative Biology, LC Miall Building, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK

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BMC Medical Genetics 2009, 10:104  doi:10.1186/1471-2350-10-104

Published: 13 October 2009

Abstract

Background

Malignant hyperthermia (MH) is an inherited pharmacogenetic disorder of skeletal muscle, characterised by an elevated calcium release from the skeletal muscle sarcoplasmic reticulum. The dihydropyridine receptor (DHPR) plays an essential role in excitation-contraction coupling and calcium homeostasis in skeletal muscle. This study focuses on the gene CACNA1S which encodes the α1 subunit of the DHPR, in order to establish whether CACNA1S plays a major role in MH susceptibility in the UK.

Methods

We investigate the CACNA1S locus in detail in 50 independent MH patients, the largest study to date, to identify novel variants that may predispose to disease and also to characterise the haplotype structure across CACNA1S.

Results

We present CACNA1S cDNA sequencing data from 50 MH patients in whom RYR1 mutations have been excluded, and subsequent mutation screening analysis. Furthermore we present haplotype analysis of unphased CACNA1S SNPs to (1) assess CACNA1S haplotype frequency differences between susceptible MH cases and a European control group and (2) analyse population-based association via clustering of CACNA1S haplotypes based on disease risk.

Conclusion

The study identified a single potentially pathogenic change in CACNA1S (p.Arg174Trp), and highlights that the haplotype structure across CACNA1S is diverse, with a high degree of variability.