Malignant hyperthermia in North America: Genetic screening of the three hot spots in the type I ryanodine receptor gene

Yoshitatsu Sei, Nyamkhishig N. Sambuughin, Edward J. Davis, Daniel Sachs, Phil B. Cuenca, Barbara W. Brandom, Timothy J Tautz, Henry Rosenberg, Thomas E. Nelson, Sheila M. Muldoon

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Abstract

Background: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle, manifested as a life-threatening hypermetabolic crisis after exposure to anesthetics. Type 1 ryanodine receptor 1 Is the primary gene responsible for susceptibility to MH as well as central core disease, a congenital myopathy that predisposes susceptibility to MH. More than 40 mutations in the RyR1 gene cluster in three coding regions: the N-terminus, central, and C-terminus regions. However, the frequency of mutations in each region has not been studied in the North American MH-susceptible population. Methods: The authors tested 124 unrelated patients with MH susceptibility for the presence of mutations in the N-terminus (exons 2, 6, 9, 11, 12, and 17), central (exons 39, 40, 44, 45, and 46), and C-terminus (exons 95, 100, 101, and 102) regions. Results: Fourteen mutations have been identified in 29 of 124 MH-susceptible patients (23%). Approximately 70% of the mutations, which include a novel mutation, Ala 2437Val, were in the central region. In 8 patients (28%), mutations were identified in the N-terminus region. Screening the C-terminus region yielded a novel mutation, Leu4824Pro, in a single patient with a diagnosis of central core disease. Conclusions: The detection rate for mutations is only 23% by screening mutations (or exons) listed in the 2002 North American consensus panel. The implications from this study suggest that testing the central region first is currently the most effective screening strategy for the North American population. Screening more exons in the three hot spots may be needed to find an accurate frequency of mutations in the RyR1 gene.

Original languageEnglish (US)
Pages (from-to)824-830
Number of pages7
JournalAnesthesiology
Volume101
Issue number4
DOIs
StatePublished - Oct 2004

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Malignant Hyperthermia
Ryanodine Receptor Calcium Release Channel
Genetic Testing
North America
Mutation
Exons
Genes
Central Core Myopathy
Mutation Rate
Myotonia Congenita
Pharmacogenetics
Multigene Family
Population
Anesthetics
Skeletal Muscle

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Sei, Y., Sambuughin, N. N., Davis, E. J., Sachs, D., Cuenca, P. B., Brandom, B. W., ... Muldoon, S. M. (2004). Malignant hyperthermia in North America: Genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology, 101(4), 824-830. https://doi.org/10.1097/00000542-200410000-00005

Malignant hyperthermia in North America : Genetic screening of the three hot spots in the type I ryanodine receptor gene. / Sei, Yoshitatsu; Sambuughin, Nyamkhishig N.; Davis, Edward J.; Sachs, Daniel; Cuenca, Phil B.; Brandom, Barbara W.; Tautz, Timothy J; Rosenberg, Henry; Nelson, Thomas E.; Muldoon, Sheila M.

In: Anesthesiology, Vol. 101, No. 4, 10.2004, p. 824-830.

Research output: Contribution to journalArticle

Sei, Y, Sambuughin, NN, Davis, EJ, Sachs, D, Cuenca, PB, Brandom, BW, Tautz, TJ, Rosenberg, H, Nelson, TE & Muldoon, SM 2004, 'Malignant hyperthermia in North America: Genetic screening of the three hot spots in the type I ryanodine receptor gene', Anesthesiology, vol. 101, no. 4, pp. 824-830. https://doi.org/10.1097/00000542-200410000-00005
Sei, Yoshitatsu ; Sambuughin, Nyamkhishig N. ; Davis, Edward J. ; Sachs, Daniel ; Cuenca, Phil B. ; Brandom, Barbara W. ; Tautz, Timothy J ; Rosenberg, Henry ; Nelson, Thomas E. ; Muldoon, Sheila M. / Malignant hyperthermia in North America : Genetic screening of the three hot spots in the type I ryanodine receptor gene. In: Anesthesiology. 2004 ; Vol. 101, No. 4. pp. 824-830.
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title = "Malignant hyperthermia in North America: Genetic screening of the three hot spots in the type I ryanodine receptor gene",
abstract = "Background: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle, manifested as a life-threatening hypermetabolic crisis after exposure to anesthetics. Type 1 ryanodine receptor 1 Is the primary gene responsible for susceptibility to MH as well as central core disease, a congenital myopathy that predisposes susceptibility to MH. More than 40 mutations in the RyR1 gene cluster in three coding regions: the N-terminus, central, and C-terminus regions. However, the frequency of mutations in each region has not been studied in the North American MH-susceptible population. Methods: The authors tested 124 unrelated patients with MH susceptibility for the presence of mutations in the N-terminus (exons 2, 6, 9, 11, 12, and 17), central (exons 39, 40, 44, 45, and 46), and C-terminus (exons 95, 100, 101, and 102) regions. Results: Fourteen mutations have been identified in 29 of 124 MH-susceptible patients (23{\%}). Approximately 70{\%} of the mutations, which include a novel mutation, Ala 2437Val, were in the central region. In 8 patients (28{\%}), mutations were identified in the N-terminus region. Screening the C-terminus region yielded a novel mutation, Leu4824Pro, in a single patient with a diagnosis of central core disease. Conclusions: The detection rate for mutations is only 23{\%} by screening mutations (or exons) listed in the 2002 North American consensus panel. The implications from this study suggest that testing the central region first is currently the most effective screening strategy for the North American population. Screening more exons in the three hot spots may be needed to find an accurate frequency of mutations in the RyR1 gene.",
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T2 - Genetic screening of the three hot spots in the type I ryanodine receptor gene

AU - Sei, Yoshitatsu

AU - Sambuughin, Nyamkhishig N.

AU - Davis, Edward J.

AU - Sachs, Daniel

AU - Cuenca, Phil B.

AU - Brandom, Barbara W.

AU - Tautz, Timothy J

AU - Rosenberg, Henry

AU - Nelson, Thomas E.

AU - Muldoon, Sheila M.

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N2 - Background: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle, manifested as a life-threatening hypermetabolic crisis after exposure to anesthetics. Type 1 ryanodine receptor 1 Is the primary gene responsible for susceptibility to MH as well as central core disease, a congenital myopathy that predisposes susceptibility to MH. More than 40 mutations in the RyR1 gene cluster in three coding regions: the N-terminus, central, and C-terminus regions. However, the frequency of mutations in each region has not been studied in the North American MH-susceptible population. Methods: The authors tested 124 unrelated patients with MH susceptibility for the presence of mutations in the N-terminus (exons 2, 6, 9, 11, 12, and 17), central (exons 39, 40, 44, 45, and 46), and C-terminus (exons 95, 100, 101, and 102) regions. Results: Fourteen mutations have been identified in 29 of 124 MH-susceptible patients (23%). Approximately 70% of the mutations, which include a novel mutation, Ala 2437Val, were in the central region. In 8 patients (28%), mutations were identified in the N-terminus region. Screening the C-terminus region yielded a novel mutation, Leu4824Pro, in a single patient with a diagnosis of central core disease. Conclusions: The detection rate for mutations is only 23% by screening mutations (or exons) listed in the 2002 North American consensus panel. The implications from this study suggest that testing the central region first is currently the most effective screening strategy for the North American population. Screening more exons in the three hot spots may be needed to find an accurate frequency of mutations in the RyR1 gene.

AB - Background: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle, manifested as a life-threatening hypermetabolic crisis after exposure to anesthetics. Type 1 ryanodine receptor 1 Is the primary gene responsible for susceptibility to MH as well as central core disease, a congenital myopathy that predisposes susceptibility to MH. More than 40 mutations in the RyR1 gene cluster in three coding regions: the N-terminus, central, and C-terminus regions. However, the frequency of mutations in each region has not been studied in the North American MH-susceptible population. Methods: The authors tested 124 unrelated patients with MH susceptibility for the presence of mutations in the N-terminus (exons 2, 6, 9, 11, 12, and 17), central (exons 39, 40, 44, 45, and 46), and C-terminus (exons 95, 100, 101, and 102) regions. Results: Fourteen mutations have been identified in 29 of 124 MH-susceptible patients (23%). Approximately 70% of the mutations, which include a novel mutation, Ala 2437Val, were in the central region. In 8 patients (28%), mutations were identified in the N-terminus region. Screening the C-terminus region yielded a novel mutation, Leu4824Pro, in a single patient with a diagnosis of central core disease. Conclusions: The detection rate for mutations is only 23% by screening mutations (or exons) listed in the 2002 North American consensus panel. The implications from this study suggest that testing the central region first is currently the most effective screening strategy for the North American population. Screening more exons in the three hot spots may be needed to find an accurate frequency of mutations in the RyR1 gene.

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