title: A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees.
abstract: 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.
authors.affiliation: Department of Biology, University of Leeds, UK. rrobinso@hgmp.mrc.ac.uk
authors.forename: R L
authors.initials: RL
authors.lastname: Robinson
authors.forename: N
authors.initials: N
authors.lastname: Monnier
authors.forename: W
authors.initials: W
authors.lastname: Wolz
authors.forename: M
authors.initials: M
authors.lastname: Jung
authors.forename: A
authors.initials: A
authors.lastname: Reis
authors.forename: G
authors.initials: G
authors.lastname: Nuernberg
authors.forename: J L
authors.initials: JL
authors.lastname: Curran
authors.forename: K
authors.initials: K
authors.lastname: Monsieurs
authors.forename: P
authors.initials: P
authors.lastname: Stieglitz
authors.forename: L
authors.initials: L
authors.lastname: Heytens
authors.forename: R
authors.initials: R
authors.lastname: Fricker
authors.forename: C
authors.initials: C
authors.lastname: van Broeckhoven
authors.forename: T
authors.initials: T
authors.lastname: Deufel
authors.forename: P M
authors.initials: PM
authors.lastname: Hopkins
authors.forename: J
authors.initials: J
authors.lastname: Lunardi
authors.forename: C R
authors.initials: CR
authors.lastname: Mueller
mesh_terms: D015220:Calcium Channels / Q000235:genetics*; D020746:Calcium Channels, L-Type; D002878:Chromosomes, Human, Pair 1; D002895:Chromosomes, Human, Pair 5; D003198:Computer Simulation; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D010375:Pedigree
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type