Mutations in<i>RYR1</i>in malignant hyperthermia and central core disease

Robinson, Rachel; Carpenter, Danielle; Shaw, Marie‐Anne; Halsall, Jane; Hopkins, Philip M.

doi:10.1002/humu.20356

Cited by 437 publications

(394 citation statements)

References 117 publications

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“…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. 6 By comparison, we found that p.Arg614Cys, p.Gly341Arg, and p.Gly2434Arg are the most frequent mutations in the Canadian MHS population, accounting for almost 35% of mutation-positive families. This outcome is not unexpected since these mutations are common in Germany, France, and the UK (Table 3), and individuals of Western European origin comprised [60% of our study group.…”

Section: Discussionmentioning

confidence: 83%

“…44 This mutation was linked to MH in two unrelated families from two different populations. 6 Moreover, several other MH-associated mutations are located in the same region. [45][46][47] The second mutation, p.Val4842Met, maps to the last transmembrane segment that forms a part of the Ca 2?…”

Section: Discussionmentioning

confidence: 99%

“…3,4 Since MH was first recognized as an inherited condition in 1960, 5 at least six potential genetic loci for MH susceptibility have been proposed. 6 However, MH-associated mutations have been found in only two genes, the RYR1 gene (MIM 180 901) on chromosome 19q13.1 encoding the calcium release channel of the sarcoplasmic reticulum, also known as the ryanodine receptor type 1 (RyR1), and the CACNA1S gene (MIM 114 208) on chromosome 1q32 encoding the a1-subunit of the voltage-gated calcium channel, also known as the dihydropyridine receptor. Both RyR1 and dihydropyridine receptors play key roles in the processes of excitationcontraction coupling and maintenance of Ca 2?…”

Section: Résumémentioning

confidence: 99%

“…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%

“…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. 12 The number of MH-and CCD-associated RYR1 mutations continues to grow and, in our current estimate, includes some 300 mutations.…”

Section: Résumémentioning

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: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Résumémentioning

confidence: 99%

Section: Résumémentioning

confidence: 99%

Section: Résumémentioning

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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Malignant Hyperthermia and Central Core Disease

McCarthy

2011

Encyclopedia of Life Sciences

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Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disorder triggered by certain types of anaesthetic agents. Genetic and biochemical evidence show that defects in the skeletal muscle ryanodine receptor calcium release channel account for most cases of MH and the related myopathy central core disease (CCD). Analysis of mutant receptors shows that these disorders are largely explained by abnormalities in ryanodine receptor‐mediated calcium release and have identified three distinct classes of channel defects. Most MH and mild CCD mutations make the ryanodine receptor hypersensitive to drug stimulation and in some instances heat. A second class of mutations, which are rarer make the channel significantly deficient in calcium release in response to depolarisation in muscle and are essentially excitation–contraction uncoupling type mutations. The third class of mutation which are also rare have been associated with recessive multimini core disease (MmD) and core myopathy and lead to a decrease in the stability of the RyR1 complex causing partial depletion of RyR1 channels expressed in skeletal muscle. Key Concepts: Malignant hyperthermia is a pharmacogenetic disorder triggered by anaesthetics and manifests as a rapid increase in body temperature and metabolism accompanied by contracture of skeletal muscles. Central core disease is closely associated with malignant hyperthermia and presents as muscle weakness at infancy and the presence of cores in muscle fibres. The ryanodine receptor is the central channel in skeletal muscle responsible for release of calcium from the sarcoplasmic reticulum into the myoplasm. The ryanodine receptor is physically coupled to the dihydropyridine receptor. The latter is located in the t‐tubules and is a voltage‐gated calcium release channel. Depolarisation of the t‐tubular membrane causes a conformational change in the dihydropyridine receptor which interlocks with the ryanodine receptor to open its calcium release channel. The released calcium cause muscle contraction. Human and animal genetics have shown that mutations in the ryanodine receptor account for most cases of malignant hyperthermia and central core disease whereas mutations in the alpha channel of the dihydropyridine receptor account for a small number of malignant hyperthermia cases. The ryanodine receptor mutations causing malignant hyperthermia and central core disease fall into three classes. The first class of mutations are most common and make the ryanodine receptor hypersensitive to drug stimulation and in some instances heat. The second class of mutations make the channel significantly deficient in calcium release in response to depolarisation. The third class of mutation lead to a decrease in the stability of the RyR1 complex.

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Molecular Genetics of Nemaline Myopathy

Sandaradura

North

2012

Encyclopedia of Life Sciences

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Nemaline myopathy (NM) is a rare neuromuscular condition characterised by muscle weakness, hypotonia, depressed or absent deep tendon reflexes and nemaline bodies (rods) on skeletal muscle biopsy. There are six clinical subtypes, ranging from a severe congenital form to a milder phenotype with onset in childhood or adulthood. Pathogenic mutations have been described to date in 8 genes, the majority of which encode protein components of the muscle thin filam ent , and there is evidence of further genetic heterogeneity. Genotype–phenotype correlation is limited. Inheritance may be autosomal dominant or autosomal recessive and de novo dominant mutations are common. The most common genetic causes are autosomal recessive mutations in NEB and de novo autosomal dominant mutations in ACTA1. There is significant overlap between subtypes and variability in severity of manifestations. Animal models have assisted understanding of pathogenesis. Key Concepts: NM is one of the most common forms of congenital myopathy. Typical clinical features include weakness, hypotonia and depressed or absent deep tendon reflexes. Inheritance may be autosomal recessive, autosomal dominant or sporadic (new dominant). Mutations in 8 genes have been associated with NM, and there is evidence of further genetic heterogeneity. Autosomal dominant mutations in ACTA1 and autosomal recessive mutations in NEB are the most common known genetic causes. Current understanding of genotype–phenotype correlation is limited. Molecular genetic testing and prenatal diagnosis are available clinically. Clinical and histological features assist prioritisation of molecular genetic testing. New technology, such as exome sequencing, will aid gene discovery and molecular diagnosis in NM.

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Mutations inRYR1in malignant hyperthermia and central core disease

Cited by 437 publications

References 117 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

Malignant Hyperthermia and Central Core Disease

Molecular Genetics of Nemaline Myopathy

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