Screening for mutations in the RYR1 gene in families with malignant hyperthermia
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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.
Index EntriesMalignant hyperthermia RYR1 gene
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- 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar
- Terwilliger J. D. and Ott J. (1994) Handbook of Human Genetic Linkage, 1st ed., John Hopkins University Press, London, UK.Google Scholar