The role of CACNA1Sin predisposition to malignant hyperthermia

Danielle Carpenter,Philip M Hopkins,P Jane Halsall,Marie-Anne Shaw,Andrew Morris,Rachel L Robinson,Vincenzo Leo,Christopher Ringrose

doi:10.1186/1471-2350-10-104

Abstract

BackgroundMalignant 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.MethodsWe 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.ResultsWe 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.ConclusionThe 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.

Highlights

Malignant hyperthermia (MH) is an inherited pharmacogenetic disorder of skeletal muscle, characterised by an elevated calcium release from the skeletal muscle sarcoplasmic reticulum
The aim of this study is to investigate the CACNA1S locus in detail and to determine whether CACNA1S may play a major role in MH susceptibility in the UK
We present analysis using unphased CACNA1S SNP data directly to (1) assess CACNA1S haplotype frequency differences between MH susceptible cases and a population control group and (2) to analyse population-based association via clustering of CACNA1S haplotypes based on disease risk

Summary

Introduction

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. Malignant hyperthermia (MH) is an inherited disorder of skeletal muscle, which predisposes to an increased release of calcium into the myoplasm under certain pharmacological conditions. BMC Medical Genetics 2009, 10:104 http://www.biomedcentral.com/1471-2350/10/104 abolic acidosis, rhabdomyolysis and a rapid rise in body temperature. This condition is potentially fatal if not recognised and treated promptly. Within skeletal muscle the sarcoplasmic reticulum (SR) controls the process of Ca2+ release, playing a major role in the process of excitation-contraction (E-C) coupling. During an MH crisis an elevated rate of cellular Ca2+ release from the SR is observed due, in part, to a reduced activation and increased deactivation threshold of the RyR1 [3], or from uncoupling of the DHPR-RyR1 interaction [4]

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