By the introduction of technological advancement in methods of structural analysis, electronics, and recombinant DNA techniques, research in physiology has become molecular Additionally, focus of interest has been moving away from classical physiology to become increasingly centered on mechanisms of disease A wonderful example for this development, as evident by this review, is the field of ion channel research which would not be nearly as advanced had it not been for human diseases to clarify It is for this reason that structure-function relationships and ion channel electrophysiology cannot be separated from the genetic and clinical description of ion channelopathies Unique among reviews of this topic is that all known human hereditary diseases of voltage-gated ion channels are described covering various fields of medicine such as neurology (nocturnal frontal lobe epilepsy, benign neonatal convulsions, episodic ataxia, hemiplegic migraine, deafness, stationary night blindness), nephrology (X-linked recessive nephrolithiasis, Bartter), myology (hypokalemic and hyperkalemic periodic paralysis, myotonia congenita, paramyotonia, malignant hyperthermia), cardiology (LQT syndrome), and interesting parallels in mechanisms of disease emphasized Likewise, all types of voltage-gated ion channels for cations (sodium, calcium, and potassium channels) and anions (chloride channels) are described together with all knowledge about pharmacology, structure, expression, isoforms, and encoding genes

/pdf/voltage-gated-ion-channels-and-hereditary-disease-55cvp1p8nq.pdf

Voltage-Gated Ion Channels and Hereditary Disease

The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation-contraction coupling and skeletal muscle calcium homeostasis. Mapping to chromosome 19q13.2, the gene comprises 106 exons and encodes a protein of 5,038 amino acids. Mutations in the gene have been found in association with several diseases: the pharmacogenetic disorder, malignant hyperthermia (MH); and three congenital myopathies, including central core disease (CCD), multiminicore disease (MmD), and in an isolated case of a congenital myopathy characterized on histology by cores and rods. The majority of gene mutations reported are missense changes identified in cases of MH and CCD. In vitro analysis has confirmed that alteration of normal calcium homeostasis is a functional consequence of some of these changes. Genotype-phenotype correlation studies performed using data from MH and CCD patients have also suggested that mutations may be associated with a range of disease severity phenotypes. This review aims to summarize the current understanding of RYR1 mutations reported in association with MH and CCD and the present viewpoint on the use of mutation data to aid clinical diagnosis of these conditions.

Mutations in RYR1 in malignant hyperthermia and central core disease.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that manifests in response to anesthetic triggering agents. Central core disease (CCD) is a myopathy closely associated with MH. Both MH and CCD are primarily disorders of calcium regulation in skeletal muscle. The ryanodine receptor (RYR1) gene encodes the key channel which mediates calcium release in skeletal muscle during excitation-contraction coupling, and mutations in this gene are considered to account for susceptibility to MH (MHS) in more than 50% of cases and in the majority of CCD cases. To date, 22 missense mutations in the 15,117 bp coding region of the RYR1 cDNA have been found to segregate with the MHS trait, while a much smaller number of these mutations is associated with CCD. The majority of RYR1 mutations appear to be clustered in the N-terminal amino acid residues 35-614 (MH/CCD region 1) and the centrally located residues 2163-2458 (MH/CCD region 2). The only mutation identified outside of these regions to date is a single mutation associated with a severe form of CCD in the highly conserved C-terminus of the gene. All of the RYR1 mutations result in amino acid substitutions in the myoplasmic portion of the protein, with the exception of the mutation in the C-terminus, which resides in the lumenal/transmembrane region. Functional analysis shows that MHS and CCD mutations produce RYR1 abnormalities that alter the channel kinetics for calcium inactivation and make the channel hyper- and hyposensitive to activating and inactivating ligands, respectively. The likely deciding factors in determining whether a particular RYR1 mutation results in MHS alone or MHS and CCD are: sensitivity of the RYR1 mutant proteins to agonists; the level of abnormal channel-gating caused by the mutation; the consequential decrease in the size of the releasable calcium store and increase in resting concentration of calcium; and the level of compensation achieved by the muscle with respect to maintaining calcium homeostasis. From a diagnostic point of view, the ultimate goal of development of a simple non-invasive test for routine diagnosis of MHS remains elusive. Attainment of this goal will require further detailed molecular genetic investigations aimed at solving heterogeneity and discordance issues in MHS; new initiatives aimed at identifying modulating factors that influence the penetrance of clinical MH in MHS individuals; and detailed studies aimed at describing the full epidemiological picture of in vitro responses of muscle to agents used in diagnosis of MH susceptibility.

Ryanodine receptor mutations in malignant hyperthermia and central core disease.

In excitation-contraction (E-C) coupling, various types of activation signals, which are received presumably at the bulky cytoplasmic domain of the ryanodine receptor (RyR), are translated (or transduced) into the opening of the Ca2+ release channel located in the trans-membrane domain of the RyR. In order to elucidate the detailed mechanism of the signal transduction process, it is essential (i) to identify various sub-domains of the RyR that are involved in the Ca2+ channel regulation, (ii) to characterize the events occurring in these sub-domains during the activation process, and (iii) to characterize the modes of active interactions among these sub-domains. Recent developments in the E-C coupling research have provided us with new insight into each of these aspects, as outlined in this review. Of many putative regulatory sub-domains of the RyR, two domains (designated as N-terminal domain and central domain) are particularly interesting, because disease-linked mutations that have occurred in these domains (malignant hyperthermia and central core disease in skeletal muscle, and inheritable cardiac disease) induce abnormal modes of Ca2+ channel regulation. Pieces of evidence accumulated to this date suggest the following hypothesis. The N-terminal and central domains form, at least partly, the interacting domain pair, and unzipping and zipping actions of such domain-pair are involved in the opening and closing actions of the Ca2+ channel, respectively. We also propose that there are local conformational changes in the signal reception domains (e.g. the II-III loop-binding core), and such conformational changes are coupled with the aforementioned actions of the interacting domain pair. It seems that by virtue of such a coordination of the events occurring in various regions of the RyR, the Ca2+ channel can recognize the activation signal received at the cytoplasmic region of the RyR.

Regulation of calcium release by interdomain interaction within ryanodine receptors.

Malignant hyperthermia (MH) in man is an autosomal dominant disorder of skeletal muscle Ca 2+ -regulation. During anesthesia in predisposed individuals, it is triggered by volatile anesthetics and depolarizing muscle relaxants. In >50% of the families, MH susceptibility is linked to the gene encoding the skeletal muscle ryanodine receptor (RYR1), the calcium release channel of the sarcoplasmic reticulum, on chromosome 19q12-13.2. To date, 21 RYR1 mutations have been Identified in a number of pedigrees. Four of them are also associated with central core disease (CCD), a congenital myopathy. Screening for these 21 mutations in 105 MH families including 10 CCD families phenotyped by the in vitro contracture test (IVCT) according to the European protocol revealed the following approximate distribution: 9% Arg-614-Cys, 1% Arg-614-Leu, 1% Arg-2163-Cys, 1% Val-2168-Met, 3% Thr-2206-Met and 7% Gly-2434-Arg. In one CCD family, the disease was caused by a recently reported MH mutation, Arg-2454-His. Two novel mutations, Thr-2206-Arg and Arg-2454-Cys were detected, each in a single pedigree. In the 109 individuals of the 25 families with RYR1 mutations cosegregation between genetic result and IVCT was almost perfect, only three genotypes were discordant with the IVCT phenotypes, suggesting a true sensitivity of 98.5% and a specificity of minimally 81.8% for this test. Screening of the transmembraneous region of RYR1 did not yield a new mutation confirming the cytosolic portion of the protein to be of main functional importance for disease pathogenesis.

/pdf/screening-of-the-ryanodine-receptor-gene-in-105-malignant-1ozob6pr6h.pdf

Screening of the Ryanodine Receptor Gene in 105 Malignant Hyperthermia Families: Novel Mutations and Concordance with the in Vitro Contracture Test

Malignant hyperthermia (MH) is a potentially fatal autosomal dominant disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalation anaesthetics and depolarizing neuromuscular blocking agents. To date, eight mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in malignant hyperthermia susceptible (MHS) and central core disease (CCD) cases. We have screened the RYR1 gene in affected individuals for novel MHS mutations by single stranded conformational polymorphism (SSCP) analysis and have identified a G to T transition mutation which results in the replacement of a conserved arginine (Arg) at position 614 with a leucine (Leu). The Arg614Leu mutation was present in three unrelated MHS individuals of 151 investigated. The mutation was not detected in 148 normal chromosomes and segregated precisely with MHS in family members from one of the probands where DNA was available for analysis. This mutation occurs at the same position as the previously identified Arg to Cys mutation reported in all cases of porcine MH and in approximately 5% of human MH. A comparison of the phenotypes of the Arg614Leu and Arg614Cys probands is presented.

Detection of a novel mutation at amino acid position 614 in the ryanodine receptor in malignant hyperthermia.

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Detection of a novel mutation at amino acid position 614 in the ryanodine receptor in malignant hyperthermia.