Evidence for the localization of a malignant hyperthermia susceptibility locus (MHS2) to human chromosome 17q

Levitt, Roy C.; Olckers, Antonel; Meyers, Samuel P.; Fletcher, J E; Rosenberg, Henry; Isaacs, H; Meyers, Deborah A.

doi:10.1016/s0888-7543(05)80152-1

Cited by 133 publications

(56 citation statements)

References 29 publications

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“…Linkage of MH to the sodium channel a-subunit gene (SCN4A) on human chromosome 17q in several families makes this gene a candidate [49]. Demonstrated defects of the sodium channel a-subunit protein leading to myotonia fluctuans, can also be associated with abnormal responses to succinylcholine, including muscle rigidity [50,51].…”

Section: T H E M O L E C U L a R B A S I S F O R M A L I G N A N T H mentioning

confidence: 99%

Ca²⁺ signalling and muscle disease

MacLennan

2000

European Journal of Biochemistry

221

155

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Transient elevations of intracellular Ca2+ play a signalling role in such complex cellular functions as contraction, secretion, fertilization, proliferation, metabolism, heartbeat and memory. However, prolonged elevation of Ca2+ above about 10 µm is deleterious to a cell and can activate apoptosis. In muscle, there is a narrow window of Ca2+ dysregulation in which abnormalities in Ca2+ regulatory proteins can lead to disease, rather than apoptosis. Key proteins in the regulation of muscle Ca2+ are the voltage‐dependent, dihydropyridine‐sensitive, l‐type Ca2+ channels located in the transverse tubule and Ca2+ release channels in the junctional terminal cisternae of the sarcoplasmic reticulum. Abnormalities in these proteins play a key role in malignant hyperthermia (MH), a toxic response to anesthetics, and in central core disease (CCD), a muscle myopathy. Sarco(endo)plasmic reticulum Ca2+ ATPases (SERCAs) return sarcoplasmic Ca2+ to the lumen of the sarcoplasmic reticulum. Loss of SERCA1a Ca2+ pump function is one cause of exercise‐induced impairment of the relaxation of skeletal muscle, in Brody disease. Phospholamban expressed in cardiac muscle and sarcolipin expressed in skeletal muscle regulate SERCA activity. Studies with knockout and transgenic mice show that gain of inhibitory function of phospholamban alters cardiac contractility and could be a causal feature in some cardiomyopathies. Calsequestrin, calreticulin, and a series of other acidic, lumenal, Ca2+ binding proteins provide a buffer for Ca2+ stored in the sarcoplasmic reticulum. Overexpression of cardiac calsequestrin leads to cardiomyopathy and ablation of calreticulin alters cardiac development.

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Section: T H E M O L E C U L a R B A S I S F O R M A L I G N A N T H mentioning

confidence: 99%

Ca²⁺ signalling and muscle disease

MacLennan

2000

European Journal of Biochemistry

221

155

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“…Rare cases of mutations in the α1 subunit of the DHPR gene (CACNA1S: MIM# 114208) have been reported in MH patients Stewart et al, 2001]. Additional loci have also been linked to MH, but causative genes have still to be identified [Levitt et al, 1992;Iles et al, 1994;Sudbrak et al, 1995;Robinson et al, 1998]. In recent years, more than 60 mutations in RYR1 have been identified in MH/CCD families [Hamilton, 2005].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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Communicated by Maria Rita Passos-BuenoMalignant 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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“…Discordance between CHCT and genetic studies has already been reported (26)(27)(28)(29)(30), indicating that some familial mutations are not found in some MHS members of the family. It is also possible that this discordant individual has another mutation in another part of RYR1 not analyzed or in another gene related to MH (4)(5)(6)(7). Some families that display more than one causative mutation leading to MH have been reported (16,31).…”

Section: Discussionmentioning

confidence: 99%

“…MH susceptibility has been linked to several loci in the genome (4)(5)(6)(7)(8), but most cases are associated with the RYR1 gene located on chromosome 19 (9,10), one of the largest and most complex genes in the human genome, comprising 106 exons and transcribing a 15,117 nucleotide-long RNA (11), which encodes a 563-kD homotetrameric protein. Worldwide, about 70-80% of MH-susceptible (MHS) individuals have mutations in RYR1 (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene

Matos

Sambuughin

Rumjanek

et al. 2009

Braz J Med Biol Res

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Evidence for the localization of a malignant hyperthermia susceptibility locus (MHS2) to human chromosome 17q

Cited by 133 publications

References 29 publications

Ca²⁺ signalling and muscle disease

Ca²⁺ signalling and muscle disease

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

Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene

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Evidence for the localization of a malignant hyperthermia susceptibility locus (MHS2) to human chromosome 17q

Cited by 133 publications

References 29 publications

Ca2+ signalling and muscle disease

Ca2+ signalling and muscle disease

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

Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene

Contact Info

Product

Resources

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Ca²⁺ signalling and muscle disease

Ca²⁺ signalling and muscle disease