Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility.
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.
Monnier
Nicole
N
Laboratoire de Biochimie Génétique et Moléculaire, INSERM U607, Grenoble, France.
Kozak-Ribbens
Geneviève
G
Krivosic-Horber
Renée
R
Nivoche
Yves
Y
Qi
Dong
D
Kraev
Natasha
N
Loke
Julian
J
Sharma
Parveen
P
Tegazzin
Vincenzo
V
Figarella-Branger
Dominique
D
Roméro
Norma
N
Mezin
Paulette
P
Bendahan
David
D
Payen
Jean-François
JF
Depret
Thierry
T
Maclennan
David H
DH
Lunardi
Joël
J
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
C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium