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Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy.

Abstract
Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene (RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype-genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings.
AuthorsN Kraeva, L Heytens, H Jungbluth, S Treves, N Voermans, E Kamsteeg, C Ceuterick-de Groote, J Baets, S Riazi
JournalNeuromuscular disorders : NMD (Neuromuscul Disord) Vol. 25 Issue 7 Pg. 567-76 (Jul 2015) ISSN: 1873-2364 [Electronic] England
PMID25958340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier B.V. All rights reserved.
Chemical References
  • Ryanodine Receptor Calcium Release Channel
Topics
  • Adult
  • Child
  • Child, Preschool
  • Family
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heterozygote
  • Humans
  • Leg (pathology)
  • Male
  • Malignant Hyperthermia (genetics, metabolism, pathology)
  • Middle Aged
  • Muscle, Skeletal (metabolism, pathology)
  • Myopathy, Central Core (genetics, metabolism, pathology)
  • Phenotype
  • Ryanodine Receptor Calcium Release Channel (genetics, metabolism)
  • White People (genetics)

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