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

Abstract

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.

Analysis of histomorphology in malignant hyperthermia-susceptible patients

“…The percentage of MHS patients with Defined as any patient with a documented adverse anesthetic reaction at the time of referral à Defined as muscle pains or cramps/spasms and/or weakness § Only the most frequent individual components of ''frank'' myopathy in the data set are presented k These patients are further described in Table 3 CHCT = caffeine-halothane contracture test; MH = malignant hyperthermia; MHS = malignant hyperthermia-susceptible; RYR1 = ryanodine receptor 1 gene (17) 47 ( and MH causative mutations [17][18][19] was within the range of previous data sets. There were no consistent histological features among MHS patients; however, more MH probands were found in the group with abnormal histomorphology, and a small subset of patients with evidence of ''frank'' myopathic abnormalities showed multiple similarities involving both historical (clinical history, signs and symptoms, and MH proband status) and biochemical (CK levels) features, CHCT results, and, in the majority of cases, evidence of a known MH-causative mutation in the RYR1 gene.…”

Ecstacy‐induced delayed rhabdomyolysis and neuroleptic malignant syndrome in a patient with a novel variant in the ryanodine receptor type 1 gene

“…With parental consent, using the mRNA extracted from the patient's peripheral blood leucocytes, we amplified it by RT-PCR and sequenced directly the PCR fragments covering the complete RYR1 transcript [1,2]. The patient's sequences were then compared with the reference RYR1 transcript sequence (GenBank Accession Number NM_000540.2) and RYR1 gene sequence (GenBank Accession Number NC_000019.8).…”

Continued progress in understanding the molecular genetics of malignant hyperthermia

“…2 Although the inheritance pattern of MH in humans was known by the 1980s, a turning point in the MH story occurred in 1990 when Dr. MacLennan's team identified the mutation in the ryanodine receptor gene causal for MH in the swine model of MH. 3 However, the molecular genetics of MH in humans has proven to be far more complex and obscure.…”

“…That has been done for 30 ryanodine mutations. The effort to distinguish causal mutations from those that are not pathologic continues in several labs around the world and is one of the objectives of the study by MacLennan et al 2 In order to select mutations most likely to disrupt normal cell function, a variety of bioinformatics tools have been developed to assess those more likely to represent a change in a protein that will significantly disrupt calcium flux. Those more likely to be pathologic (as shown in Table 2 of the paper) may then be selected for more rigorous functional characterization.…”

“…continuent de développer des travaux précédemment réalisés sur l'HM, particulièrement sur la génétique moléculaire de l'HM et la myopathie qui y est associée, la myopathie congénitale à axe central. 2 Bien que le rôle de l'hérédité de l'HM chez l'humain soit connu depuis les années 1980, un tournant dans l'histoire de l'HM est survenu en 1990 lorsque l'équipe du Dr MacLennan a identifié une mutation des gènes récepteurs de la ryanodine provoquant l'HM dans un modèle porcin d'HM. 3 Cependant, la génétique moléculaire de l'HM chez l'humain s'est avérée bien plus complexe et plus obscure.…”