Movatterモバイル変換

[0]ホーム
URL:

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

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Wolters Kluwer full text link Wolters Kluwer Free PMC article
Full text links

Actions

Share

Case Reports
.2011 Nov;115(5):938-45.
doi: 10.1097/ALN.0b013e3182320068.

Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families

Affiliations
Case Reports

Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families

Linda Groom et al. Anesthesiology.2011 Nov.

Abstract

Background: Mutations in the type 1 ryanodine receptor gene (RYR1) result in malignant hyperthermia, a pharmacogenetic disorder typically triggered by administration of anesthetics. However, cases of sudden death during exertion, heat challenge, and febrile illness in the absence of triggering drugs have been reported. The underlying causes of such drug-free fatal "awake" episodes are unknown.

Methods: De novo R3983C variant in RYR1 was identified in two unrelated children who experienced fatal, nonanesthetic awake episodes associated with febrile illness and heat stress. One of the children also had a second novel, maternally inherited D4505H variant located on a separate haplotype. Effects of all possible heterotypic expression conditions on RYR1 sensitivity to caffeine-induced Ca release were determined in expressing RYR1-null myotubes.

Results: Compared with wild-type RYR1 alone (EC50 = 2.85 ± 0.49 mM), average (± SEM) caffeine sensitivity of Ca release was modestly increased after coexpression with either R3983C (EC50 = 2.00 ± 0.39 mM) or D4505H (EC50 = 1.64 ± 0.24 mM). Remarkably, coexpression of wild-type RYR1 with the double mutant in cis (R3983C-D4505H) produced a significantly stronger sensitization of caffeine-induced Ca release (EC50 = 0.64 ± 0.17 mM) compared with that observed after coexpression of the two variants on separate subunits (EC50 = 1.53 ± 0.18 mM).

Conclusions: The R3983C mutation potentiates D4505H-mediated sensitization of caffeine-induced RYR1 Ca release when the mutations are in cis (on the same subunit) but not when present on separate subunits. Nevertheless, coexpression of the two variants on separate subunits still resulted in a ∼2-fold increase in caffeine sensitivity, consistent with the observed awake episodes and heat sensitivity.

PubMed Disclaimer

Figures

Figure 1
Figure 1
A) Pedigrees of two unrelated families with a child that experienced fatal, nonanesthetic episodes. Filled symbols with a bisecting line indicate individuals that died from a nonanesthetic episode; empty symbols represent clinically healthy family members. R or C - denote arginine or cysteine residue at position 3983; D or H - denote an aspartic acid or histidine residue at position 4505. The haplotype was constructed on the basis of genotyping with microsatellite markers D19S191, D19S224, D19S220, and D19S47. The marker order is from centromere to telomere. The parentheses for the proband in family #1 indicate that the relative location of the 3983C haplotype is unknown. In family #2, the 3983C and 4505H variants were located on different alleles and the R4505H variant was associated with the maternal 10-1-7-1 haplotype. B) Alignment of the region of ryanodine receptor (RYR) variants and flanking residues across species and RYR isoforms. The mutated residues are shown in bold. Nonconserved residues across RYR isoforms are shaded.
Figure 2
Figure 2
Effect of coexpressing either the R3893C or D4505H variants with wild-type (WT) type 1 ryanodine receptor (RYR1) in dyspedic myotubes on the caffeine sensitivity of sarcoplasmic reticulum Ca2+ release. A–C) Representative caffeine concentration responses in dyspedic myotubes expressing (A) WT RYR1 alone (n=34), (B) WT RYR1+R3893C (n=30), and (C) WT RYR1+D4505H (n=24). (D) Average (±SEM) caffeine concentration-response curves for the conditions shown in A–C.
Figure 3
Figure 3
Effect of co-expressing both the R3893C and D4505H variants together with wild-type (WT) type 1 ryanodine receptor (RYR1) in dyspedic myotubes on the caffeine sensitivity of sarcoplasmic reticulum Ca2+ release. A–C) Representative caffeine concentration responses in dyspedic myotubes expressing (A) wild-type RYR1 alone (n=34), (B) R3893C+D4505H (n=25), and (C) WT RYR1+R3893C-D4505H (n=14). (D) Average (± SEM) caffeine concentration-response curves for the conditions shown in A–C.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Rosenberg H, Sambuughin N, Dirksen RT. GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright. Seattle: University of Washington; 1997–2010. Malignant hyperthermia susceptibility. - PubMed
    1. Robinson RL, Carpenter D, Shaw M, Halsall J, Hopkins P. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat. 2006;27:977–989. - PubMed
    1. Brown RL, Pollock AN, Couchman KG, Hodges M, Hutchinson DO, Waaka R, Lynch P, McCarthy TV, Stowell KM. A novel ryanodine receptor mutation and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maori pedigree. Hum Mol Genet. 2000;12:1515–1524. - PubMed
    1. Gener B, Burns JM, Griffin S, Boyer EW. Administration of ondansetron is associated with lethal outcome. Pediatrics. 2010;125:E1514–E1517. - PubMed
    1. Nishino H, Nishio H, Sato T, Fukunishi S, Tamura A, Iwata M, Tsuboi K, Suzuki K. Identification of malignant hyperthermia-susceptible ryanodine receptor type 1 gene (RYR1) mutations in a child who died in a car after exposure to a high environmental temperature. Leg Med. 2009;11:142–143. - PubMed

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full text links
Wolters Kluwer full text link Wolters Kluwer Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp