A Genome Wide Search for Susceptibility Loci in Three European Malignant Hyperthermia Pedigrees

Robinson, Rachel; Monnier, Nicole; Wolz, Werner; Jung, Martin; Reis, André; Nuernberg, Gudrun; Curran, Julie; Monsieurs, Koenraad G.; Stieglitz, P.; Heytens, L.; Fricker, Ruth; Broeckhoven, Christine Van; Deufel, Thomas; Hopkins, Phil; Lunardi, Joël; Mueller, C.W.

doi:10.1093/hmg/6.6.953

Cited by 105 publications

(50 citation statements)

References 28 publications

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“…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]. Extensive searches have been carried out to identify other MH loci [52].…”

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

218

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

218

155

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“…Molecular genetic studies have mapped the primary locus of MH to chromosome 19q 13.1, to the gene encoding the ryanodine receptor calcium channel (RYR1; MIM# 180901) (MacLennan et al 1990;McCarthy et al 1990). Linkage studies however, have revealed MH as a heterogenetic disease (Levitt et al 1991;Deufel et al 1992;Monnier et al 1997;Robinson et al 1997); in fact mutation screenings have so far identified 23 distinct mutations in the RYR1 and approximately 50% of MH families are estimated to have mutations in the RYR1 gene (McCarthy et al 1990;MacLennan and Phillips 1992;Robinson et al 1997;Manning et al 1998b;Jurkat-Rott et al 2000;McCarthy et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Genotype-phenotype comparison of the Swiss malignant hyperthermia population

et al. 2001

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Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disease, triggered by inhalative anesthetics or depolarizing muscle relaxants in genetically predisposed individuals. Linkage analysis have revealed MH to be a heterogenetic disease with about 50% of MH families linked to the locus of the ryanodine receptor calcium channel (RYR1). We investigated the frequency of the 23 published MH linked RYR1 gene mutations in the Swiss MH population and compared our findings to the results of the in vitro contracture test (IVCT). IVCT was performed following the protocol of the European MH Group and mutation screening was done by PCR amplification of genomic DNA followed by restriction enzyme digestion or SSCP. We identified RYR1 gene mutations in 40% of unrelated MH families (19/48) with a high incidence of the mutation V2168M (27%). IVCT results revealed a significantly stronger functional effect of mutations R614C and V2168M as compared to mutations G2434R and R2458C. This is the first time that such a high incidence of RYR1 gene mutations in an MH population has been found, supporting the use of molecular genetic testing for the diagnosis of MH susceptibility in suitable families. In addition our data show that different RYR1 gene mutations are associated with different IVCT phenotypes.

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“…29 A systematic linkage study using a set of polymorphic microsatellite markers covering the entire human genome in a small number of large, apparently non-chromosome 19 linked European MH families, identified a locus on chromosome 3q13.1 (MHS4), 70 a locus on chromosome 1q (MHS5), 50 59 and a tentative locus on chromosome 5q (MHS6). 59 A causative gene at the MHS3 and MHS4 locus has yet to be identified. The CACNL1A3 gene encodes the a1-subunit of the DHP receptor maps to the MHS5 locus and functions as a voltage gated channel.…”

Section: Ryanodine Receptor (Ryr1)mentioning

confidence: 99%