title: Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility.
abstract: Malignant hyperthermia susceptibility (MHS) is a subclinical pharmacogenetic disorder caused by an impairment of skeletal muscle calcium homeostasis in response to triggering agents. While in vitro contracture testing (IVCT) is the gold standard for defining MHS, molecular analysis is increasingly used to diagnosis MHS. Mutations associated with MHS have been reported in two genes: RYR1 and CACNA1S. Mutations in RYR1 are also responsible for central core disease (CCD), a myopathy that can be associated with a positive IVCT response. We report here the results of correlation studies performed with molecular, pharmacological, histological, and functional data obtained in 175 families (referred to as confirmed (129) or potential (46) MHS families). Extensive molecular analysis allowed us to identify a variant in 60% of the confirmed MHS families, and resulted in the characterization of 11 new variants in the RYR1 gene. Most mutations clustered to MH1 and MH2 domains of RYR1. Functional analysis allowed us to assign a causative role for seven MHS mutations that we propose to add to the panel of MHS mutations used for genetic testing. The use of genetic data to determine MHS status led to a 99.5% sensitivity for IVCT. IVCT-positive/mutation-negative diagnoses were analyzed not only in terms of specificity for IVCT, but also to assess the presence of a second MHS trait in families, and the genetic heterogeneity of the disease. Histological analyses revealed the presence of cores in more than 20% of muscle biopsies originating from 242 genotyped and tested MHS patients who did not present with clinical symptoms. This indicates that these patients must be considered as MHS patients with cores, and are clearly differentiated from CCD patients who have been tested positive for MHS.
authors.affiliation: Laboratoire de Biochimie Génétique et Moléculaire, INSERM U607, Grenoble, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Monnier
authors.forename: Geneviève
authors.initials: G
authors.lastname: Kozak-Ribbens
authors.forename: Renée
authors.initials: R
authors.lastname: Krivosic-Horber
authors.forename: Yves
authors.initials: Y
authors.lastname: Nivoche
authors.forename: Dong
authors.initials: D
authors.lastname: Qi
authors.forename: Natasha
authors.initials: N
authors.lastname: Kraev
authors.forename: Julian
authors.initials: J
authors.lastname: Loke
authors.forename: Parveen
authors.initials: P
authors.lastname: Sharma
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tegazzin
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.forename: Norma
authors.initials: N
authors.lastname: Roméro
authors.forename: Paulette
authors.initials: P
authors.lastname: Mezin
authors.forename: David
authors.initials: D
authors.lastname: Bendahan
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Payen
authors.forename: Thierry
authors.initials: T
authors.lastname: Depret
authors.forename: David H
authors.initials: DH
authors.lastname: Maclennan
authors.forename: Joël
authors.initials: J
authors.lastname: Lunardi
mesh_terms: D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics; D020746:Calcium Channels, L-Type; D002460:Cell Line; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D017434:Protein Structure, Tertiary; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics
chemical_list: C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium