Human Molecular Genetics, Vol 6, 953-961, Copyright © 1997 by Oxford University Press
RL Robinson, N Monnier, W Wolz, M Jung, A Reis, G Nuernberg, JL Curran, K Monsieurs, P Stieglitz, L Heytens, R Fricker, C van Broeckhoven, T Deufel, PM Hopkins, J Lunardi and CR Mueller
Malignant hyperthermia (MH) is an autosomal dominant disorder which is
potentially lethal in susceptible individuals on exposure to commonly used
inhalational anaesthetics and depolarising muscle relaxants. Crises reflect
the consequences of disturbed skeletal muscle calcium homeostasis.
Susceptibility was first localised to chromosome 19q13.1 and the skeletal
muscle ryanodine receptor, RYR1 (the calcium release channel of the
sarcoplasmic reticulum). Defects in this gene have been identified which
cosegregate with the MHS phenotype and evidence as to their potential
causal roles has accumulated. MH has, however, been shown to be genetically
heterogeneous, additional loci on chromosomes 3q, 17q and 7q being
proposed. Pedigrees remain in Europe where linkage status is still unclear.
In a collaborative search of the human genome conducted with three
pedigrees whose disease status was classified according to the European
IVCT protocol we have evidence to suggest that at least two further loci
exist for MH susceptibility. One of these locates to chromosome 1q, the
site of a candidate gene, CACNL1A3, encoding the alpha-subunit of the
dihydropyridine receptor. The second region resides on chromosome 5p to
where no known candidate has been mapped to date. The third family
exhibited inconclusive results which suggests the existence of at least one
other locus. This study adds to the evidence for considerable genetic
heterogeneity in MH and will provide a route to further our understanding
of the molecular pathology of the condition.
ARTICLES
A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees
Department of Biology, University of Leeds, UK. rrobinso@hgmp.mrc.ac.uk
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