Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2001 Jul;69(1):204-8.
doi: 10.1086/321270. Epub 2001 May 29.

Single-amino-acid deletion in the RYR1 gene, associated with malignant hyperthermia susceptibility and unusual contraction phenotype

N Sambuughin  1 , S McWilliams, A de Bantel, K Sivakumar, T E Nelson
Affiliations

Single-amino-acid deletion in the RYR1 gene, associated with malignant hyperthermia susceptibility and unusual contraction phenotype

N Sambuughin et al. Am J Hum Genet. 2001 Jul.

Abstract

Malignant hyperthermia (MH) is an anesthetic-drug-induced, life-threatening hypermetabolic syndrome caused by abnormal calcium regulation in skeletal muscle. Often inherited as an autosomal dominant trait, MH has linkage to 30 different mutations in the RYR1 gene, which encodes a calcium-release-channel protein found in the sarcoplasmic reticulum membrane in skeletal muscle. All published RYR1 mutations exclusively represent single-nucleotide changes. The present report documents, in exon 44 of RYR1 in two unrelated, MH-susceptible families, a 3-bp deletion that results in deletion of a conserved glutamic acid at position 2347. This is the first deletion, in RYR1, found to be associated with MH susceptibility. MH susceptibility was confirmed among some family members by in vitro diagnostic pharmacological contracture testing of biopsied skeletal muscle. Although a single-amino-acid deletion appears to be a subtle change in the protein, the deletion of Glu2347 from RYR1 produces an unusually large electrically evoked contraction tension in MH-positive individuals, suggesting that this deletion produces an alteration in skeletal-muscle calcium regulation, even in the absence of pharmacological agents.

PubMed Disclaimer

Figures

Figure 1
Figure 1
A, Sequence analysis of cloned PCR product, revealing a 3-bp deletion (GGA). The upper chromatogram shows a sequence of DNA, from the proband in family 1, with the deletion. The arrow indicates the site of the deletion. The lower chromatogram shows a sequence of DNA, from individual 1 in family 2, without the deletion. B, Amino acid comparison of RYR1 region flanking the deleted residue. The asterisk (*) indicates glutamic acid (E) deleted at 2347.
Figure 2
Figure 2
Pedigrees of two families with MH-positive-plus phenotype. Blackened circles and squares denote patients who had either a clinical episode of MH or positive muscle-biopsy contracture-test results; the unblackened empty circle denotes a family member who was not studied; circles and square with a question mark denote family members studied genetically but in whom contracture testing was not performed; arrows indicate the probands. Haplotypes were constructed on the basis of the markers, with the following order: D20S220 (top), an intragenic TaqI polymorphism in RYR1 exon 20, presence (a) or absence (A) of the deletion, and D20S47. Segregation of the deletion was analyzed by BseRI digestion of a 252-bp PCR product of exon 44, as shown on the agarose gel below the pedigrees. The deletion was detected by loss of a BseRI site, resulting in the generation of 252-bp, 173-bp, and 79-bp DNA fragments. The first lane on the left represents a 100-bp marker ladder.
Figure 3
Figure 3
A–C, Distribution of in vitro electrically evoked contractions in skeletal muscle from groups that are MH negative (A), MH positive plus (B), and MH positive with and/or without deletion (C). Individual fascicle responses were graphed in order of increasing contraction tension (in g force). Not all individuals in MH-positive groups have been screened for deletion, which, therefore, may or may not be present. To the right of the graphs, the percentages of total fascicles in given ranges of tension level are denoted. D, Distribution of isometric-twitch force in fascicles 391, 573, and 46, forming, respectively, MH-negative (solid curve/filled circles), MH-positive (dotted curve/open circles), and MH-positive-plus (dashed curve/triangles) phenotypes in RYR1. Force ranges are 0–2 g, 2–5 g, 5–10 g, 10–14 g, 14–28 g, and 28–38 g. Each group has a bimodal distribution of twitch forces, with most MH-negative and MH-positive twitch forces occurring in the range of 2–14 g and with the MH-positive-plus twitch forces showing a higher percentage of forces in the range of 14–28 g.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

Electronic-Database Information

    1. Center for Medical Genetics, Marshfield Medical Research Foundation, http://research.marshfieldclinic.org/genetics/ (for chromosome 19 markers)
    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for human skeletal-muscle RYR1 exon 44 sequence [accession number U48477], RYR1 sequence [accession number J05200], cardiac-muscle RYR2 sequence [accession number X98330], dog skeletal-muscle RYR1 sequence [accession numbers AF302182 and AF302129], and pig skeletal-muscle RYR1 sequence [accession number M91452])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for MH [MIM 145600], human RYR1 [MIM 180901], and central core disease [MIM 117000])

References

    1. Allen GC, Larach MG, Kunselman AR (1998) The sensitivity and specificity of the caffeine-halothane contracture test. Anesthesiology 88:579–588 - PubMed
    1. Allen PD, Ryan JF, Jones DE, Mabuchi K, Virga A, Roberts J, Sreter F (1986) Sarcoplasmic reticulum calcium uptake in cryostat section of skeletal muscle from malignant hyperthermia patients and controls. Muscle Nerve 5:474–475 - PubMed
    1. Brown RL, Pollock AN, Couchman KG, Hodges M, Hutchinson DO, Waaka R, Lynch P, McCarty TV, Stowell KM (2000) A novel ryanodine receptor mutation and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maori pedigree. Hum Mol Genet 9:1515–1524 - PubMed
    1. Chamley D, Pollock NA, Stowell KM, Brown RL (2000) Malignant hyperthermia in infancy and identification of novel RYR1 mutation. Br J Anaesth 84:500–504 - PubMed
    1. Etchrivi TS, Adnet PJ, Tavernier B, Diallo A, Haudecoeur G, Krivosic-Horber RM (1998) Effects of halothane on mechanical response of skeletal muscle from malignant hyperthermia susceptible patients. Arch Physiol Biochem 106:1–7 - PubMed

MeSH terms

Substances