Article

Frequency and localization of mutations in the 106 exons of theRYR1 gene in 50 individuals with malignant hyperthermia

Molecular Medicine Section, Department of Neuroscience, University of Siena and Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Human Mutation (Impact Factor: 5.05). 08/2006; 27(8):830. DOI: 10.1002/humu.9442
Source: PubMed

ABSTRACT Malignant hyperthermia (MH) is a dominantly inherited pharmacogenetic condition that manifests as a life-threatening hypermetabolic reaction when a susceptible individual is exposed to common volatile anesthetics and depolarizing muscle relaxants. Although MH appears to be genetically heterogeneous, RYR1 is the main candidate for MH susceptibility. However, since molecular analysis is generally limited to exons where mutations are more frequently detected, these are routinely found only in 30-50% of susceptible subjects. In this study the entire RYR1 coding region was analyzed in a cohort of 50 Italian MH susceptible (MHS) subjects. Thirty-one mutations, 16 of which were novel, were found in 43 individuals with a mutation detection rate of 86%, the highest reported for RYR1 in MH so far. These data provide clear evidence that mutations in the RYR1 gene are the predominant cause of MH.

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Available from: Alfredo Orrico, Oct 08, 2014
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    • "The CASQ1 variant (NM 001231.4:c.731A>G) has been submitted to the locusspecific database (www.lovd.nl/CASQ1). Mutation screening of the RyR1 gene was performed as previously described in Galli et al. (2006). Haplotype analysis was based on the following intragenic SNPs: rs617698, rs61803844, rs617599, rs3747621, rs3747622, rs3747623, and rs822450. "
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    • "The CASQ1 variant (NM 001231.4:c.731A>G) has been submitted to the locusspecific database (www.lovd.nl/CASQ1). Mutation screening of the RyR1 gene was performed as previously described in Galli et al. (2006). Haplotype analysis was based on the following intragenic SNPs: rs617698, rs61803844, rs617599, rs3747621, rs3747622, rs3747623, and rs822450. "
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    ABSTRACT: A missense mutation in the calsequestrin-1 gene (CASQ1) was found in a group of patients with a myopathy characterized by weakness, fatigue and the presence of large vacuoles containing characteristic inclusions resulting from the aggregation of sarcoplasmic reticulum (SR) proteins. The mutation affects a conserved aspartic acid in position 244 (p.Asp244Gly) located in one of the high-affinity Ca2+ binding sites of CASQ1 and alters the kinetics of Ca2+ release in muscle fibers. Expression of the mutated CASQ1 protein in COS-7 cells showed a markedly reduced ability in forming elongated polymers, while both in cultured myotubes and in in-vivo mouse fibers induced the formation of electron-dense SR vacuoles containing aggregates of the mutant CASQ1 protein that resemble those observed in muscle biopsies of patients. Altogether, these results support the view that a single missense mutation in the CASQ1 gene causes the formation of abnormal SR vacuoles containing aggregates of CASQ1 and other SR proteins, results in altered Ca2+ release in skeletal muscle fibers and, hence, is responsible for the clinical phenotype observed in these patients.This article is protected by copyright. All rights reserved
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    • "1 44 c.7085A>G p.E2362G No Galli et al. 2006 [30] "
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    ABSTRACT: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro. A total of 200 patients met the inclusion criteria. Two MH crises (1%) were triggered by SCh (1 MHS, 1 MHE), 18% by volatile anesthetics and 81% by a combination of both. Patients were 70% male and 50% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles. An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.
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