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

In swine, a point mutation in the ryanodine receptor gene can account for all cases of malignant hyperthermia (MH). The frequency of a corre sponding mutation in humans (C1840-T) and its relationship to the in v itro contracture profile is unknown. We screened 192 patients from 28 unrelated northern German families for the C1840-T mutation in the hum an 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 nonsuscepti ble and 30 MH equivocal status following IVCT. In each family one or t wo 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 a s the contracture profiles following cumulative (0.4-10.0 mu mol/l eve ry 3 min) and bolus (10 mu mol/l) administration of ryanodine were fou nd 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 profil es in the presence and absence of this mutation might imply no major f unctional role with respect to the contracture response. At present, m olecular genetic analysis cannot replace IVCT to discover MH susceptib ility in humans.