title: C1840-T mutation in the human skeletal muscle ryanodine receptor gene: frequency in northern German families susceptible to malignant hyperthermia and the relationship to in vitro contracture response.
abstract: In swine, a point mutation in the ryanodine receptor gene can account for all cases of malignant hyperthermia (MH). The frequency of a corresponding mutation in humans (C1840-T) and its relationship to the in vitro contracture profile is unknown. We screened 192 patients from 28 unrelated northern German families for the C1840-T mutation in the human ryanodine receptor gene and tested for MH susceptibility using the in vitro contracture test (IVCT) according to the European MH Protocol. In our patients 106 revealed MH susceptible (MHS), 56 MH nonsusceptible and 30 MH equivocal status following IVCT. In each family one or two individuals had developed clinical signs of MH or a MH crisis. All of these patients were classified MHS. The C1840-T mutation was found in 2 of 28 families (7.1%). All eight individuals of the two families characterized by this mutation revealed MHS status following IVCT. The thresholds for halothane- and caffeine-induced contractures as well as the contracture profiles following cumulative (0.4-10.0 mumol/l every 3 min) and bolus (10 mumol/l) administration of ryanodine were found to be similar in MHS patients with and without the C1840-T mutation. In conclusion, the C1840-T mutation in the human ryanodine receptor gene is a rare abnormality in MHS families. Similar contracture profiles in the presence and absence of this mutation might imply no major functional role with respect to the contracture response. At present, molecular genetic analysis cannot replace IVCT to discover MH susceptibility in humans.
authors.affiliation: Abteilung für Anästhesiologie, Universität Hamburg, Universitäts-Krankenhaus Eppendorf.
authors.forename: M
authors.initials: M
authors.lastname: Steinfath
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.forename: J
authors.initials: J
authors.lastname: Scholz
authors.forename: K
authors.initials: K
authors.lastname: Becker
authors.forename: C
authors.initials: C
authors.lastname: Lenzen
authors.forename: F
authors.initials: F
authors.lastname: Wappler
authors.forename: A
authors.initials: A
authors.lastname: Köchling
authors.forename: N
authors.initials: N
authors.lastname: Roewer
authors.forename: J
authors.initials: J
authors.lastname: Schulte am Esch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002110:Caffeine / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002888:Chromosomes, Human, Pair 19; D004198:Disease Susceptibility; D005260:Female; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects*; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000737:chemistry* / Q000187:drug effects; D017354:Point Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel
chemical_list: D015220:Calcium Channels; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D002110:Caffeine; D006221:Halothane