Several interacting genes influence the malignant hyperthermia phenotype

Robinson, Rachel; Hopkins, Philip M.; Carsana, Antonella; Gilly, H.; Halsall, Jane; Heytens, L.; Islander, Gunilla; Jurkat‐Rott, Karin; Müller, C. R.; Shaw, Marie‐Anne

doi:10.1007/s00439-002-0864-6

Cited by 49 publications

(23 citation statements)

References 3 publications

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“…One explanation for discordancy in IVCT tested MH susceptible individuals is that there are some as yet undiscovered variants in RYR1 or CACNA1S or other genes, which contribute to MH phenotype, while modifier loci have been implicated 39,40 : NGS may help to resolve discordancy in some families.…”

Section: Discussionmentioning

confidence: 99%

Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness

et al. 2015

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Background Variants in RYR1 are associated with the majority of cases of malignant hyperthermia (MH), a form of heat illness pharmacogenetically triggered by general anesthetics, and they have also been associated with exertional heat illness. CACNA1S has also been implicated in MH. We applied a targeted next generation sequencing approach to identify variants in RYR1 and CACNA1S in a cohort of unrelated patients diagnosed with MH susceptibility. We also provide the first comprehensive report of sequencing of these two genes in a cohort of survivors of exertional heat illness. Methods DNA extracted from blood was genotyped using a “long” polymerase chain reaction technique, with sequencing on the Illumina GAII® or MiSeq® platforms (Illumina Inc., San Diego, CA). Variants were assessed for pathogenicity using bioinformatic approaches. For further follow up DNA from additional family members and up to 211 MH normal and 556 MH susceptible unrelated individuals was tested. Results In 29 MH patients we identified three pathogenic and four novel RYR1 variants, with a further five RYR1 variants previously reported in association with MH. Three novel RYR1 variants were found in the exertional heat illness cohort (n = 28) along with two more previously reported in association with MH. Two other variants were reported previously associated with centronuclear myopathy. We found one and three rare variants of unknown significance in CACNA1S in the MH and exertional heat illness cohorts respectively. Conclusion Targeted next generation sequencing proved efficient at identifying diagnostically useful and potentially implicated variants in RYR1 and CACNA1S in MH and exertional heat illness.

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Section: Discussionmentioning

confidence: 99%

Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness

et al. 2015

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“…1994; Robinson et al. 2003), a causal role for this mutation was ruled out on the basis of its predicted dominance and its predicted benign effect, but mainly on the basis of its absence in the affected sibling.…”

Section: Resultsmentioning

confidence: 99%

“…A new, c. 2974C>T, p.His992Tyr, mutation was detected in CAC-NA2D1 (NM_000722). Although this gene encodes the a2/ o subunit of the skeletal muscle Ca 2+ channel and is located within a chromosomal region linked to MHS (Iles et al 1994;Robinson et al 2003), a causal role for this mutation was ruled out on the basis of its predicted dominance and its predicted benign effect, but mainly on the basis of its absence in the affected sibling.…”

Section: Genetic Analysis and Whole Exome Resultsmentioning

confidence: 99%

Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility

Sambuughin

Zvaritch

Kraeva

et al. 2014

Molec Gen & Gen Med

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Whole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a family diagnosed with a mild, undetermined myopathy and malignant hyperthermia (MH) susceptibility (MHS). WES revealed the compound heterozygous mutations, p.Ile235Asn and p.Glu982Lys, in ATP2A1, encoding the sarco(endo)plasmic reticulum Ca2+ ATPase type 1 (SERCA1), a calcium pump, expressed in fast-twitch muscles. Recessive mutations in ATP2A1 are known to cause Brody myopathy, a rare muscle disorder characterized by exercise-induced impairment of muscle relaxation and stiffness. Analyses of affected muscles showed the absence of SERCA1, but SERCA2 upregulation in slow and fast myofibers, suggesting a compensatory mechanism that partially restores the diminished Ca2+ transport in Brody myopathy. This compensatory adaptation to the lack of SERCA1 Ca2+ pumping activity within the muscle explains, in part, the mild course of disease in our patient. Diagnosis of MHS in this family was secondary to a loss of SERCA1 due to disease-associated mutations. Although there are obvious differences in clinical expression and molecular mechanisms between MH and Brody myopathy, a feature common to both conditions is elevated myoplasmic Ca2+ content. Prolonged intracellular Ca2+ elevation is likely to have led to MHS diagnosis in vitro and postoperative MH-like symptoms in Brody patient.

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“…In agreement with previous studies aiming at investigating the potential contribution of new drugs to the diagnosis of MH, control subjects were those of MH families members with negative halothane‐caffeine results (17, 23). We did not choose to select control subjects on the basis of genetic results because (i) for roughly 50% of MH susceptible subjects, mutation is still unknown, (ii) some families have been identified where the IVCT phenotype and the susceptibility genotype are discordant (5, 24), and (iii) several studies have reported that multiple genes may influence susceptibility to MH in individual families (24, 25). These considerations are further confirmed by our comparative analysis of IVCT and genetic results performed in a subgroup of subjects.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of in vitro contracture tests with ryanodine and a combination of ryanodine with either halothane or caffeine: a comparative investigation in malignant hyperthermia

Bendahan

Guis

Monnier³

et al. 2004

Acta Anaesthesiol Scand

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Several interacting genes influence the malignant hyperthermia phenotype

Cited by 49 publications

References 3 publications

Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness

Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness

Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility

Comparative analysis of in vitro contracture tests with ryanodine and a combination of ryanodine with either halothane or caffeine: a comparative investigation in malignant hyperthermia

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