Ca 2+ ATPase Phospholamban, Sarcolipin Brody Disease Cardiomyopathy Ca2+ Release Channel MH/CCD Publications Ca2+ Binding Proteins OMIM MH OMIM CCD OMIM RYR1 Patent Human MH Patent Pig MH MHA Canada MHAUS European MH Group						Malignant Hyperthermia and Central Core Disease Malignant hyperthermia (MH) in humans is an abnormal response to the administration of potent inhalational anesthetics and depolarizing muscle relaxants. Major features of the syndrome are rapidly elevated temperature, cellular ion imbalance and skeletal muscle contracture. Since cytoplasmic Ca2+ is essential for muscle contracture, and since Ca2+ can also trigger metabolic events leading to heat production, it was deduced that elevated intracellular Ca2+ is a causal factor in the MH syndrome. Our studies of the genetic basis for MH began with our cloning of cDNA encoding the Ca2+ release channel of human skeletal muscle sarcoplasmic reticulum, localization of the gene (the RYR1 gene) to chromosome 19q13.1 and linkage of markers in the RYR1 gene to MH, indicating that at least some forms of human MH are caused by mutations in the RYR1 gene. Since swine are also MH susceptible, we compared the RYR1 cDNA sequences from MH normal (MHN) Yorkshire swine and MHS Pietrain swine. We found a single point mutation, the substitution of Cys for Arg615, which segregated with MH in swine in an extensive linkage study. We then searched for the corresponding mutation in humans and found the Arg614 to Cys mutation in 1 to 2% of human MH families. The finding that the mutation is so closely linked to MH in swine, together with the finding that it reappears and is also linked to MH in a second species, is powerful evidence that at least one RYR1 mutation is causal of porcine and at least some forms of human MH. Central core disease (CCD) is an autosomal dominant myopathy in which proximal muscle weakness is common. The disease is characterized by the presence of myofibrillar cores which are best demonstrated by oxidative enzyme histochemistry. An important feature of the disease is its close association with malignant hyperthermia. On the basis of linkage between CCD and the ryanodine receptor gene in large Australian and German families, we sequenced cDNA from a CCD proband and found that inheritance of the mutation of Arg2434 to His in the ryanodine receptor sequence could be linked to the inheritance of CCD in a large Canadian family. Of the 15 MH or MH plus CCD mutations identified to date, all lie between residues 35 and 614 or between amino acids 2162 and 2458 and 13 involve the gain or loss of an Arg residue. Our current goals cover the range of our interests in MH: the definition of the true MH population; the development of efficient methods for the identification of all RYR1 MH and CCD mutations; the biochemical distinction of which RYR1 mutations are likely to be causal of MH; and the development of an animal model for MH and CCD.
Ca 2+ ATPase Phospholamban, Sarcolipin Brody Disease Cardiomyopathy Ca2+ Release Channel MH/CCD Top of Page Ca2+ Binding Proteins OMIM MH OMIM CCD OMIM RYR1 Patent Human MH Patent Pig MH MHA Canada MHAUS European MH Group						MH/CCD Publications MacLennan, D.H. and Britt, B.A. (1998) Malignant hyperthermia and central core disease, in Principles of Molecular Medicine (Jameson, J.L.) MacLennan, D.H., Loke, J. and Odermatt, A. (1997) The role of genes encoding sarcoplasmic reticulum proteins in malignant hyperthermia, central core disease and Brody disease, in Calcium as a Cellular Regulator (Carafoli, E. and Klee, C.) Oxford University Press New York Loke, J. and MacLennan, D.H. (1998) Malignant hyperthermia and central core disease: disorders of Ca2+ release channels. American Journal of Medicine (in press) Loke, J.C.P., Britt, B.A. and MacLennan, D.H. (1997) Bayesian modelling of muscle biopsy contracture testing for malignant hyperthermia. Anesthesiology ((in press)): MacLennan, D.H. and Britt, B.A. (1996) Malignant hyperthermia and central core disease: Genetic and physiological basis, in Textbook of Molecular Medicine (Jameson, J.L.) Blackwell Scientific Publication Inc. Cambridge MacLennan, D.H., Phillips, M.S. and Britt, B.A. (1996) The molecular and genetic basis for malignant hyperthermia and central core disease, in The Molecular and Genetic Basis of Neurological Disease (Rosenberg, R.N., Prusiner, S.B., DiMauro, S. and Barchi, R.L.) Butterworth Heinemann Newton, MA MacLennan, D.H., Phillips, M.S. and Zhang, Y. (1996) The genetic and physiological basis of malignant hyperthermia, in Molecular Biology of Membrane Transport Disorders (Schultz, S.G., Andreoli, T.E., Brown, A.M., Fambrough, D., Hoffman, J. and M.J. Welsh) Plenum Press New York Phillips, M.S., Fujii, J., Khanna, V.K., DeLeon, S., Yokobata, K., de Jong, P. and MacLennan, D.H. (1996) The structural organization of the human skeletal muscle ryanodine receptor (RYR1) gene. Genomics 34(1):24-41 Serfas, K.D., Bose, D., Patel, L., Wrogemann, K., Phillips, M.S., MacLennan, D.H. and Greenberg, C.R. (1996) Comparison of the segregation of the RYR1 C1840T mutation with segregation of the caffeine/halothane contracture test results for malignant hyperthermia susceptibility in a large Manitoba Mennonite family [see comments]. Anesthesiology 84(2):322-9 MacLennan, D.H. (1995) Discordance between phenotype and genotype in malignant hyperthermia. Current Opinion in Neurology 8(5):397-401 MacLennan, D.H. and Phillips, M.S. (1995) The role of the skeletal muscle ryanodine receptor gene in malignant hyperthermia and central core disease, in Ryanodine Receptors (Sorrentino, V.) CRC Press Boca Raton MacLennan, D.H. and Phillips, M.S. (1995) The role of the skeletal muscle ryanodine receptor (RYR1) gene in malignant hyperthermia and central core disease, in Ion Channels and Genetic Diseases (Dawson, D.C. and Frizzell, R.A.) Rockefeller University Press New York Phillips, M.S., Khanna, V.K., De Leon, S., Frodis, W., Britt, B.A. and MacLennan, D.H. (1994) The substitution of Arg for Gly2433 in the human skeletal muscle ryanodine receptor is associated with malignant hyperthermia. Human Molecular Genetics 3(12):2181-6 MacLennan, D.H., Phillips, M.S. and Zhang, Y. (1993) The genetic basis of malignant hyperthermia, in Malignant Hyperthermia: A Genetic Membrane Disease (Ohnishi, S.T. and Ohnishi, T.) CRC Press Boca Raton Rouquier, S., Giorgi, D., Trask, B., Bergmann, A., Phillips, M.S., MacLennan, D.H. and de Jong, P. (1993) A cosmid and yeast artificial chromosome contig containing the complete ryanodine receptor (RYR1) gene. Genomics 17(2):330-40 Zhang, Y., Chen, H.S., Khanna, V.K., De Leon, S., Phillips, M.S., Schappert, K., Britt, B.A., Browell, A.K. and MacLennan, D.H. (1993) A mutation in the human ryanodine receptor gene associated with central core disease. Nature Genetics 5(1):46-50 Schwemmle, S., Wolff, K., Palmucci, L.M., Grimm, T., Lehmann-Horn, F., Hubner, C., Hauser, E., Iles, D.E., MacLennan, D.H. and Muller, C.R. (1993) Multipoint mapping of the central core disease locus. Genomics 17(1):205-7 Mulley, J.C., Kozman, H.M., Phillips, H.A., Gedeon, A.K., McCure, J.A., Iles, D.E., Gregg, R.G., Hogan, K., Couch, F.J., MacLennan, D.H. and et al. (1993) Refined genetic localization for central core disease. American Journal of Human Genetics 52(2):398-405 MacLennan, D.H., Otsu, K., Fujii, J., Zorzato, F., Phillips, M.S., PJ, O.B., Archibald, A.L., Britt, B.A., Gillard, E.F. and Worton, R.G. (1992) The role of the skeletal muscle ryanodine receptor gene in malignant hyperthermia. Symposia of the Society for Experimental Biology 46189-201 MacLennan, D.H. (1992) The genetic basis of malignant hyperthermia. Trends in Pharmacological Sciences 13(8):330-4 Deufel, T., Golla, A., Iles, D., Meindl, A., Meitinger, T., Schindelhauer, D., DeVries, A., Pongratz, D., MacLennan, D.H., Johnson, K.J. and et al. (1992) Evidence for genetic heterogeneity of malignant hyperthermia susceptibility. American Journal of Human Genetics 50(6):1151-61 Gillard, E.F., Otsu, K., Fujii, J., Duff, C., de Leon, S., Khanna, V.K., Britt, B.A., Worton, R.G. and MacLennan, D.H. (1992) Polymorphisms and deduced amino acid substitutions in the coding sequence of the ryanodine receptor (RYR1) gene in individuals with malignant hyperthermia. Genomics 13(4):1247-54 Otsu, K., Phillips, M.S., Khanna, V.K., de Leon, S. and MacLennan, D.H. (1992) Refinement of diagnostic assays for a probable causal mutation for porcine and human malignant hyperthermia. Genomics 13(3):835-7 MacLennan, D.H. and Phillips, M.S. (1992) Malignant hyperthermia. Science 256(5058):789-94 Gillard, E.F., Otsu, K., Fujii, J., Khanna, V.K., de Leon, S., Derdemezi, J., Britt, B.A., Duff, C.L., Worton, R.G. and MacLennan, D.H. (1991) A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 11(3):751-5 Otsu, K., Khanna, V.K., Archibald, A.L. and MacLennan, D.H. (1991) Cosegregation of porcine malignant hyperthermia and a probable causal mutation in the skeletal muscle ryanodine receptor gene in backcross families. Genomics 11(3):744-50 Fujii, J., Otsu, K., Zorzato, F., de Leon, S., Khanna, V.K., Weiler, J.E., PJ, O.B. and MacLennan, D.H. (1991) Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science 253(5018):448-51 MacKenzie, A.E., Allen, G., Lahey, D., Crossan, M.L., Nolan, K., Mettler, G., Worton, R.G., MacLennan, D.H. and Korneluk, R. (1991) A comparison of the caffeine halothane muscle contracture test with the molecular genetic diagnosis of malignant hyperthermia. Anesthesiology 75(1):4-8 MacKenzie, A.E., Korneluk, R.G., Zorzato, F., Fujii, J., Phillips, M., Iles, D., Wieringa, B., Leblond, S., Bailly, J., Willard, H.F., Duff, C., Worton, R.G. and MacLennan, D.H. (1990) The human ryanodine receptor gene: its mapping to 19q13.1, placement in a chromosome 19 linkage group and exclusion as the gene causing myotonic dystrophy. American Journal of Human Genetics 46(6):1082-9 MacLennan, D.H., Duff, C., Zorzato, F., Fujii, J., Phillips, M., Korneluk, R.G., Frodis, W., Britt, B.A. and Worton, R.G. (1990) Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature 343(6258):559-61
MH/CCD Top of Page Publications Revised 1998Apr09