Measurement of Resting Cytosolic Ca2+ Concentrations and Ca2+ Store Size in HEK-293 Cells Transfected with Malignant Hyperthermia or Central Core Disease Mutant Ca2+ Release Channels

Tong, Jiefei; McCarthy, Tommie V.; MacLennan, David H.

doi:10.1074/jbc.274.2.693

Cited by 194 publications

(179 citation statements)

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“…Disease mutations in RYR1 have been shown to lead to three distinct channel defects. In one class, referred to as leaky mutations, RyR1 channel activation is hypersensitive to electrical and drug stimulation (23)(24)(25). Excessive Ca 2ϩ leakage and SR store depletion might contribute to abnormalities in intracellular Ca 2ϩ homeostasis and compromise skeletal muscle function.…”

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confidence: 99%

An Ryr1 ^I4895T mutation abolishes Ca ²⁺ release channel function and delays development in homozygous offspring of a mutant mouse line

Zvaritch

Depreux

Kraeva

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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A heterozygous Ile4898 to Thr (I4898T) mutation in the human type 1 ryanodine receptor/Ca 2+ release channel (RyR1) leads to a severe form of central core disease. We created a mouse line in which the corresponding Ryr1 I4895T mutation was introduced by using a “knockin” protocol. The heterozygote does not exhibit an overt disease phenotype, but homozygous (IT/IT) mice are paralyzed and die perinatally, apparently because of asphyxia. Histological analysis shows that IT/IT mice have greatly reduced and amorphous skeletal muscle. Myotubes are small, nuclei remain central, myofibrils are disarranged, and no cross striation is obvious. Many areas indicate probable degeneration, with shortened myotubes containing central stacks of pyknotic nuclei. Other manifestations of a delay in completion of late stages of embryogenesis include growth retardation and marked delay in ossification, dermatogenesis, and cardiovascular development. Electron microscopy of IT/IT muscle demonstrates appropriate targeting and positioning of RyR1 at triad junctions and a normal organization of dihydropyridine receptor (DHPR) complexes into RyR1-associated tetrads. Functional studies carried out in cultured IT/IT myotubes show that ligand-induced and DHPR-activated RyR1 Ca 2+ release is absent, although retrograde enhancement of DHPR Ca 2+ conductance is retained. IT/IT mice, in which RyR1-mediated Ca 2+ release is abolished without altering the formation of the junctional DHPR-RyR1 macromolecular complex, provide a valuable model for elucidation of the role of RyR1-mediated Ca 2+ signaling in mammalian embryogenesis.

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confidence: 99%

An Ryr1 ^I4895T mutation abolishes Ca ²⁺ release channel function and delays development in homozygous offspring of a mutant mouse line

Zvaritch

Depreux

Kraeva

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Both MH and CCD channels with mutations in these two regions were found to be more permeable than wildtype channels. Elevations in resting Ca 21 concentrations were found to lead to elevated synthesis of SERCA2b, a compensatory mechanism aimed at the restoration of Ca 21 homeostasis [56]. MH and CCD mutant Ca 21 release channels could be distinguished by their differing permeabilities, the most highly permeable leading to the most severe forms of CCD.…”

Section: I F F E R E N T I a T I O N B E T W E E N M H A N D C C D mentioning

confidence: 99%

Ca²⁺ signalling and muscle disease

MacLennan

2000

European Journal of Biochemistry

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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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“…17 Genetic testing guidelines have been recently published by the EMHG to enable DNA diagnosis of MH in supplementation to the IVCT method of patient screening in MH families. In summary, genetic testing using certain mutations in the RYR1 gene demonstrated to be 'causative' of MH through in vitro biochemical assays, 18,19 or through linkage analysis with markers flanking the RYR1 locus is now feasible. Individuals carrying a 'causative' mutation or high-risk susceptibility haplotype are considered at risk of developing MH independent of IVCT diagnoses.…”

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Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing?

Robinson

Anetseder

Brancadoro³

et al. 2003

Eur J Hum Genet

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Malignant hyperthermia (MH) is a condition that manifests in susceptible individuals only on exposure to certain anaesthetic agents. Although genetically heterogeneous, mutations in the RYR1 gene (19q13.1) are associated with the majority of reported MH cases. Guidelines for the genetic diagnosis for MH susceptibility have recently been introduced by the European MH Group (EMHG). These are designed to supplement the muscle biopsy testing procedure, the in vitro contracture test (IVCT), which has been the only means of patient screening for the last 30 years and which remains the method for definitive diagnosis in suspected probands. Discordance observed in some families between IVCT phenotype and susceptibility locus genotype could limit the confidence in genetic diagnosis. We have therefore assessed the prevalence of 15 RYR1 mutations currently used in the genetic diagnosis of MH in a sample of over 500 unrelated European MH susceptible individuals and have recorded the frequency of RYR1 genotype/IVCT phenotype discordance. RYR1 mutations were detected in up to B30% of families investigated. Phenotype/genotype discordance in a single individual was observed in 10 out of 196 mutation-positive

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Measurement of Resting Cytosolic Ca2+ Concentrations and Ca2+ Store Size in HEK-293 Cells Transfected with Malignant Hyperthermia or Central Core Disease Mutant Ca2+ Release Channels

Abstract: Malignant hyperthermia (MH) and central core disease (CCD) mutations were introduced into full-length

Cited by 194 publications

References 45 publications

An Ryr1 ^I4895T mutation abolishes Ca ²⁺ release channel function and delays development in homozygous offspring of a mutant mouse line

An Ryr1 ^I4895T mutation abolishes Ca ²⁺ release channel function and delays development in homozygous offspring of a mutant mouse line

Ca²⁺ signalling and muscle disease

Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing?

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Measurement of Resting Cytosolic Ca2+ Concentrations and Ca2+ Store Size in HEK-293 Cells Transfected with Malignant Hyperthermia or Central Core Disease Mutant Ca2+ Release Channels

Abstract: Malignant hyperthermia (MH) and central core disease (CCD) mutations were introduced into full-length

Cited by 194 publications

References 45 publications

An Ryr1 I4895T mutation abolishes Ca 2+ release channel function and delays development in homozygous offspring of a mutant mouse line

An Ryr1 I4895T mutation abolishes Ca 2+ release channel function and delays development in homozygous offspring of a mutant mouse line

Ca2+ signalling and muscle disease

Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing?

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Product

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An Ryr1 ^I4895T mutation abolishes Ca ²⁺ release channel function and delays development in homozygous offspring of a mutant mouse line

An Ryr1 ^I4895T mutation abolishes Ca ²⁺ release channel function and delays development in homozygous offspring of a mutant mouse line

Ca²⁺ signalling and muscle disease