Screening of the Entire Ryanodine Receptor Type 1 Coding Region for Sequence Variants Associated with Malignant Hyperthermia Susceptibility in the North American Population

Sambuughin, Nyamkhishig; Holley, Heather; Muldoon, Sheila M.; Brandom, Barbara W.; Bantel, Astrid M. de; Tobin, Joseph R.; Nelson, Tom E.; Goldfarb, Lev G.

doi:10.1097/00000542-200503000-00007

Cited by 133 publications

(96 citation statements)

References 34 publications

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“…13 The high RYR1 mutation detection rate observed in this study can be explained by the stringent selection criteria for enrolment into the study and by the mutation screening strategy, which consisted of sequence analysis of complete RYR1 transcripts. Comparable detection rates (70% to 86%) have been reported recently for other MHS populations [8][9][10] where genetic screening included the entire coding sequence of the gene. On the other hand, if only established MH causative mutations from the EMHG database (www.emhg.org) were considered, then the mutation detection rates or the diagnostic sensitivity of the genetic testing would be 42% in this study and from 28% to 33% in other studies.…”

Section: Discussionsupporting

confidence: 73%

“…On the other hand, if only established MH causative mutations from the EMHG database (www.emhg.org) were considered, then the mutation detection rates or the diagnostic sensitivity of the genetic testing would be 42% in this study and from 28% to 33% in other studies. [8][9][10] This does not compare favourably with a reported sensitivity of 97% to 99% for CHCT and in vitro contracture test (IVCT), respectively. 36,37 Published data indicate that the frequency of MH-causative RyR1 mutations is population-specific, with only a few mutations accounting for the majority of MH cases in some populations.…”

Section: Discussionmentioning

confidence: 61%

“…Despite being labelled as MHS on the basis of their CHCT results and representing families with a clear history of MH, five individuals in this study (14%) carried neither mutations in RYR1 nor known mutations in CACNA1S. The absence of RYR1 mutations in MHS individuals, together with the presence of discordant cases in families C-18 and C-27 and other MH families worldwide, 8,10 may be explained by the sensitivity and specificity of the CHCT, which identifies both false negatives and false positives at a low rate. 36,37,49 Another reason might be the possible involvement of as yet unrecognized genetic and environmental factors in the MHS phenotype.…”

Section: Discussionmentioning

confidence: 80%

“…7 Malignant hyperthermia genetic research has shown that RYR1 is the major causal gene for MH as well as for a congenital myopathy, central core disease (CCD). 3,6 Malignant hyperthermia-associated RYR1 mutations have been found in 60% to 86% of MH families with diverse ethnicity, [8][9][10][11] and their distribution and frequency have been shown to be population-specific. 6 Recent improvements in molecular genetics methods have facilitated genetic analysis of the entire coding region of RYR1, which is *159,000 nucleotides long and contains 106 exons that are spliced into a 15 kb RYR1 mRNA transcript.…”

Section: Résumémentioning

confidence: 99%

“…Five other unrelated patients carried recurrent mutations not yet proven to be causal of MH, p.Arg1667Cys, 32 p.Ala2200Val, 8 p.Arg2336His, 10 p.Val4849Ile, 33 p.Gly4935 Ser. 34 One individual from this group carried a novel mutation, p.Glu209Lys, in combination with a recurrent mutation, p.Arg2336His.…”

Section: Previously Reported Ryr1 Mutationsmentioning

confidence: 99%

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Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Kraeva

Riazi

Loke

et al. 2011

Can J Anesth/J Can Anesth

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Purpose Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder that is manifested on exposure of susceptible individuals to halogenated anesthetics or succinylcholine. Since MH is associated primarily with mutations in the ryanodine receptor type 1 (RYR1) gene, the purpose of this study was to determine the distribution and frequency of MH causative RyR1 mutations in the Canadian MH susceptible (MHS) population. Methods In this study, we screened a representative cohort of 36 unrelated Canadian MHS individuals for RYR1 mutations by sequencing complete RYR1 transcripts and selected regions of CACNA1S transcripts. We then analyzed the correlation between caffeine-halothane contracture test (CHCT) results and RYR1 genotypes within MH families. Results Eighty-six percent of patients had at least one RyR1 mutation (31 out of 36), five of which were unrelated individuals who were double-variant carriers. Fifteen of the 27 mutations identified in RYR1 were novel. Eight novel mutations, involving highly conserved amino acid residues, were predicted to be causal. Two of the mutations co-segregated with the MHS phenotype within two large independent families (a total of 79 individuals). Fourteen percent of MHS individuals (five out of 36) carried neither RYR1 nor known CACNA1S mutations. Conclusions The distribution and frequency of MH causative RyR1 mutations in the Canadian MHS population are close to those of European MHS populations. Novel mutations described in this study will contribute to the worldwide pool of MH-associated mutations in the RYR1 gene, ultimately increasing the value of MH genetic diagnostic testing. RésuméObjectif L'hyperthermie maligne (HM) est une maladie pharmacoge´ne´tique he´re´ditaire dominante autosomique qui se manifeste lors de l'exposition des personnes susceptibles a`des anesthe´siques haloge´ne´s ou à la succinylcholine. E´tant donne´que l'HM est principalement associe´e aux mutations au niveau du ge`ne des re´cepteurs de ryanodine de type 1 (RYR1), l'objectif de cette e´tude e´tait de de´terminer la distribution et la fre´quence des mutations RyR1 causant une HM chez la population canadienne susceptible a`l'HM (SHM). Méthode Dans cette e´tude, nous avons examine´une cohorte repre´sentative de 36 personnes canadiennes SHM This article is accompanied by an editorial. Please see Can J Anesth 2011; 58: 6.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 80%

Section: Résumémentioning

confidence: 99%

Section: Previously Reported Ryr1 Mutationsmentioning

confidence: 99%

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Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Kraeva

Riazi

Loke

et al. 2011

Can J Anesth/J Can Anesth

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Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility

et al. 2005

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Malignant hyperthermia susceptibility (MHS) is a subclinical pharmacogenetic disorder caused by an impairment of skeletal muscle calcium homeostasis in response to triggering agents. While in vitro contracture testing (IVCT) is the gold standard for defining MHS, molecular analysis is increasingly used to diagnosis MHS. Mutations associated with MHS have been reported in two genes: RYR1 and CACNA1S. Mutations in RYR1 are also responsible for central core disease (CCD), a myopathy that can be associated with a positive IVCT response. We report here the results of correlation studies performed with molecular, pharmacological, histological, and functional data obtained in 175 families (referred to as confirmed (129) or potential (46) MHS families). Extensive molecular analysis allowed us to identify a variant in 60% of the confirmed MHS families, and resulted in the characterization of 11 new variants in the RYR1 gene. Most mutations clustered to MH1 and MH2 domains of RYR1. Functional analysis allowed us to assign a causative role for seven MHS mutations that we propose to add to the panel of MHS mutations used for genetic testing. The use of genetic data to determine MHS status led to a 99.5% sensitivity for IVCT. IVCT-positive/mutation-negative diagnoses were analyzed not only in terms of specificity for IVCT, but also to assess the presence of a second MHS trait in families, and the genetic heterogeneity of the disease. Histological analyses revealed the presence of cores in more than 20% of muscle biopsies originating from 242 genotyped and tested MHS patients who did not present with clinical symptoms. This indicates that these patients must be considered as MHS patients with cores, and are clearly differentiated from CCD patients who have been tested positive for MHS.

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Mutations inRYR1in malignant hyperthermia and central core disease

et al. 2006

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The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation-contraction coupling and skeletal muscle calcium homeostasis. Mapping to chromosome 19q13.2, the gene comprises 106 exons and encodes a protein of 5,038 amino acids. Mutations in the gene have been found in association with several diseases: the pharmacogenetic disorder, malignant hyperthermia (MH); and three congenital myopathies, including central core disease (CCD), multiminicore disease (MmD), and in an isolated case of a congenital myopathy characterized on histology by cores and rods. The majority of gene mutations reported are missense changes identified in cases of MH and CCD. In vitro analysis has confirmed that alteration of normal calcium homeostasis is a functional consequence of some of these changes. Genotype-phenotype correlation studies performed using data from MH and CCD patients have also suggested that mutations may be associated with a range of disease severity phenotypes. This review aims to summarize the current understanding of RYR1 mutations reported in association with MH and CCD and the present viewpoint on the use of mutation data to aid clinical diagnosis of these conditions.

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Screening of the Entire Ryanodine Receptor Type 1 Coding Region for Sequence Variants Associated with Malignant Hyperthermia Susceptibility in the North American Population

Cited by 133 publications

References 34 publications

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility

Mutations inRYR1in malignant hyperthermia and central core disease

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