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Screening for mutations in the RYR1 gene in families with malignant hyperthermia

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Abstract

Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic predisposition associated with a susceptibility to volatile anesthetics and depolarizing muscle relaxants that lead to a fulminant anesthetic crisis with hyperthermia, skeletal muscle rigidity, respiratory and metabolic acidosis, and muscle rhabdomyolysis. Malignant hyperthermia crises are caused by an abnormal regulation of the calcium release mechanism, which reflects the consequences of disturbed skeletal muscle calcium homeostasis. We screened 64 individuals of 27 unrelated families for the most frequently described mutations associated with MH in the genes RYR1 and CACNL1A3. We identified only one family with the Arg614Cys mutation but with a discordant segregating pattern to the in vitro contracture test (IVCT). To elucidate which other mechanism could lead to susceptibility in the members of this family, we tested it for further MH susceptibility loci. The same haplotype was shown to segregate with the individuals carrying the Arg614Cys mutation in chromosome 19; however, the other susceptible and equivocal individuals do not share this haplotype. Markers for the susceptible locus in chromosome regions 17q, 7q, 3q, and 5p did not segregate with the IVCT phenotype in the susceptible individuals, suggesting that the positivity of the IVCT could be attributable to other ambient factors.

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References

  • Barone V., Massa O., Intravaia E., Bracco A., Di Martino A., Tegazzin V., et al. (1999) Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families. J. Med. Genet. 36, 115–118.

    PubMed  CAS  Google Scholar 

  • Brandt A., Schleithoff L., Jurkat-Rott K., Klingler W., Baur C., and Lehmann-Horn F. (1999) Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test. Hum. Mol. Genet. 8, 2055–2062.

    Article  PubMed  CAS  Google Scholar 

  • Brown R. L., Pollock A. N., Couchman K. G., Hodges M., Hutchinson D. O., Waaka R., et al. (2000) A novel ryanodine receptor mutation and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maoripedigree. Hum. Mol. Genet. 9, 1515–1524.

    Article  PubMed  CAS  Google Scholar 

  • Chamley D., Pollock N. A., Stowell K. M., and Brown R. (2000) Malignant hyperthermia in infancy and identification of novel RYR1 mutation. Br. J. Anaesth. 84, 500–504.

    PubMed  CAS  Google Scholar 

  • Deufel T., Sudbrack R., Feist Y., Rubsan B., Du Chesne I., Schafer K. L., et al. (1995) Discordance, in a malignant hyperthermia pedigree, between in vitro contracture test phenotypes and haplotypes for the MHS1 region on chromosome 19q12-13.2, comprising the C1840T transition in the RYR1 gene. Am. J. Hum. Genet. 56, 1334–1342.

    PubMed  CAS  Google Scholar 

  • Fagerlund T. H., Islander G., Twetman E. R., and Berg K. (1995) A search for three known RYR1 gene mutations in 41 Swedish families with predisposition to malignant hyperthermia. Clin. Genet. 48, 12–16.

    Article  PubMed  CAS  Google Scholar 

  • Gillard E., Otsu K., Fujii J., Khanna V. K., de Leon S., Derdemezi J., et al. (1991) A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 11, 751–755.

    Article  PubMed  CAS  Google Scholar 

  • Gillard E., Otsu K., Fujii J., Duff K., de Leon S., Khanna V. K., et al. (1992) Polymorphisms and deduced amino acid substitutions in the coding sequence of the RYR1 gene in individuals with malignant hyperthermia. Genomics 13, 1247–1254.

    Article  PubMed  CAS  Google Scholar 

  • Hogan K. (1997) To fire the train: a second malignanthyperthermia gene. Am. J. Hum. Genet. 60, 1303–1308.

    PubMed  CAS  Google Scholar 

  • Jurkat-Rott K., McCarthy T., and Lehmann-Horn F. (2000) Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 23, 4–17.

    Article  PubMed  CAS  Google Scholar 

  • Keating K., Giblin L., Lynch P., Quane K., Lehane M., Heffron J., and McCarthy T. (1997) Detection of a novel mutation in the ryanodine receptor gene in an Irish malignant hyperthermia pedigree: correlation of the IVCT response with the affected and unaffected haplotypes. J. Med. Genet. 34, 291–296.

    Article  PubMed  CAS  Google Scholar 

  • Keating K., Quane K., Manning B., Lehane M., Hartung E., Censier K., et al. (1994) Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees. Hum. Mol. Genet. 10, 1855–1858.

    Article  Google Scholar 

  • Levitt R. C., Olckers A., Meyers S., Fletcher J. E., Rosemberg H., Isaacs H., and Meyers D. A. (1992) Evidence for the localization of a malignant hypethermia susceptibility locus (MSH2) to human chromosome 17q. Genomics 14, 562–566.

    Article  PubMed  CAS  Google Scholar 

  • Lynch P. J., Krivosic-Horber R., Reyford H., Monnier N., Quane K., Adnet P., et al. (1997) Identification of homozygous and heterozygous individuals with a novel RYR1 mutation in a large kindred. Anesthesiology 86, 620–626.

    Article  PubMed  CAS  Google Scholar 

  • Lynch P. J., Tong J., Lehane M., Mallet A., Giblin L., Heffron J. J., et al. (1999) A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease. Proc. Natl. Acad. Sci. USA 96, 4164–4169.

    Article  PubMed  CAS  Google Scholar 

  • MacLennan D. H. (1995) Discordance between phenotype and genotype in malignant hyperthermia. Curr. Opin. Neurol. 8, 397–401.

    Article  PubMed  CAS  Google Scholar 

  • MacLennan D. H., Duff C., Zorzato F., Fujii J., Phillips M., Korneluk R. G., et al. (1990) Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature 343, 559–561.

    Article  PubMed  CAS  Google Scholar 

  • Manning B. M., Quane K. A., Ording H., and Urwyler A. (1998) Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hypethermia: genotype-phenotype correlation. Am. J. Hum. Genet. 62, 599–601.

    Article  PubMed  CAS  Google Scholar 

  • McCarthy T. V., Healy J. M., Lehane M., and Heffron J. J. (1990) Recent developments in the molecular genetics of malignant hyperthermia: implications for future diagnosis at the DNA level. Acta Anaesthesiol. Belg. 41, 107–112.

    PubMed  CAS  Google Scholar 

  • Moleshi R., Langlois S., Yam I., and Friedman J. M. (1998) Linkage of malignant hyperthermia and hyperkalemic periodic paralysis to the adult skeletal muscle sodium channel (SCN4A) gene in a large pedigree. Am. J. Med. Genet. 76, 21–27.

    Article  Google Scholar 

  • Monnier N., Romero N. B., Lerale J., Nvoche Y., Qi D., MacLennan D. H., Fardeau M., and Lunardi J. (2000) An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum. Mol. Genet. 9, 2599–2608.

    Article  PubMed  CAS  Google Scholar 

  • Monnier N., Procaccio V., Stieglitz P., and Lunardi J. (1997) Malignant-hyperthermia susceptibility is associated with a mutation of the alpha-1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am. J. Hum. Genet. 60, 1316–1325.

    PubMed  CAS  Google Scholar 

  • Monnier N., Krivosic-Horber R., Payen J. F., Kozak-Ribbens G., Nivoche Y., Adnet P., et al. (2002) Presence of two genetic traits in MH families: implication for genetic analysis, diagnosis and incidence of malignant hyperthermia susceptibility. Anesthesiology 97, 1067–1074.

    Article  PubMed  CAS  Google Scholar 

  • Olckers A., Meyers D. A., Meyers S., Taylor E. W., Fletcher J. E., Rosenberg H., et al. (1992) Adult muscle sodium channel alpha-subunit is a gene cadidate for malignanthyperthermia susceptibility. Genomics 14, 829–831.

    Article  PubMed  CAS  Google Scholar 

  • Ording H., Brancadoro V., Cozzolino S., Ellis F. R., Glauber V., Gonano E. F., et al. (1997) In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated lowrisk subjects. Acta Anesthesiol. Scand. 41, 955–966.

    CAS  Google Scholar 

  • Phillips M. S., Fujii J., Khanna V. K., DeLeon S., Yokobata K., de Jong P. J., and MacLennan D. H. (1996) The RYR1 gene. The structural organization of the human skeletal muscle ryanodine receptor (RYR1) gene. Genomics 15, 24–41.

    Article  Google Scholar 

  • Phillips M., Khanna V. K., de Leon S., Frodis W., Britt B., and MacLennan D. (1994) The substitution of Arg for Gly 2433 in the human sjkeletal muscle ryanodine receptor is associated with malignant hyperthermia. Hum. Mol. Genet. 3, 2181–2186.

    Article  PubMed  CAS  Google Scholar 

  • Quane K. A., Healy J. M. S., Keating K. E., Manning B. M., Couch F. J., Palmucci L. M., et al. (1993) Mutations in theryanodine receptor gene in central core disease and malignant hyperthermia. Nat. Genet. 5, 51–55.

    Article  PubMed  CAS  Google Scholar 

  • Quane K. A., Keating K., Healy J. M. S., Manning B. M., Krivosic-Horber R., Krivosic I., et al. (1994) Mutation screening of the RYR1 gene in malignant hyperthermia: detection of a novel Tyr to Ser mutation in a pedigree with associated central cores. Genomics 23, 236–239.

    Article  PubMed  CAS  Google Scholar 

  • Robinson R. L., Curran J. L., Ellis F. R., Halsall P. J., Hall W. J., Hopkins P. M., et al. (2000) Multiple interacting gene products may influence susceptibility to malignant hyperthermia. Ann. Hum. Genet. 64, 307–320.

    Article  PubMed  CAS  Google Scholar 

  • Robinson R. L., Monnier N., Wolz W., Jung M., and Reis A. (1997) A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees. Hum. Mol. Genet. 6, 953–961.

    Article  PubMed  CAS  Google Scholar 

  • Rueffert H., Olthoff D., Deutrch C., and Froster U. G. (2001) Determination of a positive MH disposition without the in vitro contracture test in families carrying the RYR1 Arg614Cys mutation. Clin. Genet. 60, 117–124.

    Article  PubMed  CAS  Google Scholar 

  • Sambuughin N., McWilliams S., Bantel A., Sivakumar K., and Nelson T. E. (2001a) Single-amino-acid deletion in the RYR1 gene, associated with malignant hyperthermia susceptibility and unusual contraction phenotype. Am. J. Hum. Genet. 69, 204–208.

    Article  PubMed  CAS  Google Scholar 

  • Sambuughin N., Nelson T. E., Jankovic J., Xin C., Meissner G., Mullakandov M., et al. (2001b) Identification and funcional characterization of a novel mutation causing malignant hyperthermia in North American and South American families. Neuromuscul. Disord. 11, 530–537.

    Article  PubMed  CAS  Google Scholar 

  • Sudbrak R., Golla A., Hogan K., Powers P., Gregg R., Du Chesne I., et al. (1993) Exclusion of malignant hyperthermia susceptibility (MHS) from a putative MHS2 locus on chromosome 17q and of the alpha-1, beta-1, and gamma subunits of the dihydropyridine receptor calcium channel as candidates for the molecular defect. Hum. Mol. Genet. 2, 857–862.

    Article  PubMed  CAS  Google Scholar 

  • Sudbrak R., Procaccio V., Klausnitzer M., Curran J. L., Monsieurs K., Van Broeckhoven C., and Ellis R. (1995) Mapping of a further malignant hyperthermia susceptibility locus to chromosome 3q13.1 Am. J. Hum. Genet. 56, 684–691.

    PubMed  CAS  Google Scholar 

  • Terwilliger J. D. and Ott J. (1994) Handbook of Human Genetic Linkage, 1st ed., John Hopkins University Press, London, UK.

    Google Scholar 

  • Zhang Y., Chen H. S., Khanna V. K., De Leon S., Phillips M. S., Schappert K., et al. (1993) A mutation in the human ryanodine receptor gene associated with central core disease. Nat. Genet. 5, 46–50.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Human Genome Research Center, Department of Biology, IB, University of Sao Paulo, Sao Paulo, Brazil

    Viviane P. Muniz & Mariz Vainzof

  2. Department of Pathology, FM, University of Sao Paulo, Sao Paulo, Brazil

    Helga C. A. Silva & Ana Maria C. Tsanaclis

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  1. Viviane P. Muniz
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  2. Helga C. A. Silva
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  3. Ana Maria C. Tsanaclis
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  4. Mariz Vainzof
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Correspondence to Mariz Vainzof.

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Muniz, V.P., Silva, H.C.A., Tsanaclis, A.M.C. et al. Screening for mutations in the RYR1 gene in families with malignant hyperthermia. J Mol Neurosci 21, 35–42 (2003). https://doi.org/10.1385/JMN:21:1:35

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  • DOI: https://doi.org/10.1385/JMN:21:1:35

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