Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system

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Abstract

Some of the most common diseases in humans occur intermittently in people who are otherwise healthy and active. Such disorders include migraine headache, epilepsy, and cardiac arrythymias. Because electrical signals are critical to the function of neurons, muscle cells, and heart cells, proteins that regulate electrical signaling in these cells are logical sites where abnormalities might lead to disease. All of these diseases have prominent genetic components. Difficulty in understanding these diseases arises from the complexity of the clinical phenotypes as well as from the genetic heterogeneity that is almost certain to exist. Therefore, early work in my laboratory was aimed at understanding the pathogenesis of rare disorders that are similar in their episodic nature. These disorders of muscle (the periodic paralyses), lead to attacks of weakness that occur intermittently in otherwise normal people. We, and others, have shown that hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) result from mutations in a gene encoding a skeletal muscle sodium channel. We have also shown that hypokalemic periodic paralysis (hypoKPP) is caused by mutations in a gene encoding a voltage-gated calcium channel. The characterization of these diseases as channelopathies has served as a paradigm for other episodic disorders. One example is periodic ataxia, which results from mutations in voltage-gated potassium calcium channels. Long QT syndrome, an episodic cardiac dysrhythmia syndrome, is known to result from mutations in either voltage-gated sodium or potassium channels. We have recently mapped genes that cause a familial paroxysmal dyskinesia (non-kinesiogenic paroxysmal dystonia/choreoathetosis) in humans and a reflex epilepsy in mice. The similarities among all these disorders, including their episodic nature, precipitating factors, and therapeutic responses, are striking. Understanding gained from work in these rare monogenic episodic disorders is not only allowing characterization of the molecular and physiologic basis of these diseases, but may ultimately shed light on our understanding of the pathophysiology of more common and genetically complex disorders of the central nervous system.

Introduction

Advances in the last decade in genetics and molecular biology have led to an explosion of successful efforts directed at localizing and cloning genes that cause human diseases. The following paradigm outlines a genetic approach to human diseases:Clinicaldisorder→Genelocalization→Geneidentification→Invitrostudy→Therapeutics

Clinical characterization of hereditary disorders, and studies in families segregating alleles for these disorders, have been the critical first steps in this process. Highly polymorphic genetic markers that densely saturate the entire genome have proven critical, allowing the development of powerful genetic mapping strategies for gene localization. Once the genomic localization of a disease gene is known, both candidate gene and positional cloning strategies can be pursued in the process of gene identification. Candidate genes are ones that may be implicated in the disease based on a pathophysiologic rationale. Many genes have been cloned and mapped in the genome without knowledge of their involvement in the human disease process. If a disease gene locus maps in the region of a known gene whose function (and dysfunction) may play a role in the pathogenesis of that disorder, then identification of patient specific mutations in that gene is one step toward proving its involvement in the disease.

Mutation and polymorphism are common in the human genome, and therefore, any such mutations coincidentally occurring in a putative candidate would have a 50% chance of segregating with the disease in any given family. Therefore, it is important to use strict genetic criteria for proving involvement of a gene in hereditary disease. Such criteria include:

  • 1.

    Mutations at highly conserved residues that segregate with the disease phenotype.

  • 2.

    Identification of the same mutation in multiple families of various ethnic backgrounds.

  • 3.

    Absence of such mutations in a large number of unrelated control samples.

  • 4.

    Identification of different mutations in different families with the same disease.

  • 5.

    Identification of de novo mutations in patients with sporadic disease where parents have undergone careful clinical evaluation as well as paternity testing. (This is the single most potent genetic argument one can use in establishing the role of a gene in an autosomal dominant disease.)

Once a gene is identified the wild type protein and mutant proteins may be studied biochemically, physiologically, or in cell biology systems to identify the role of the normal protein, as well as the dysfunction of the mutant one. Ultimately, this understanding will hopefully lead to better diagnosis and treatment of hereditary disorders in humans. It is interesting that identification of one of the first human disease genes using a genetic approach was for Duchenne's muscular dystrophy [1]. Subsequently, genes that cause a multitude of other muscular dystrophies have been identified. A dramatic example of this is seen in the non-dystrophic myotonias and periodic paralyses where several genes have been identified to cause a large number of different clinical phenotypes. These included the identification of the first voltage-gated ion channel gene implicated in human disease. Subsequently, other ion channel genes have been implicated in the pathophysiology of other members of this group of muscular disorders. Furthermore, this work has now extended into work of disorders of the central nervous system and the heart, where pathophysiologically related disorders have also been shown to result from mutations in voltage- and ligand-gated ion channels.

Section snippets

Periodic paralyses/myotonias: an example of the genetic approach

The periodic paralyses include several conditions in which episodes of limb weakness occur spontaneously or are provoked by various stimuli including changes in plasma potassium, muscle cooling, and muscle activity. Some of these patients also exhibit myotonia, a form of abnormal electrical activity consisting of repetitive action potentials on electromyography associated with delayed relaxation of muscle after voluntary contraction or mechanical stimulation [2]. A disabling feature of several

Sodium channel disorders

Hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia, represent myotonic disorders due to episodic membrane hyperexcitability of skeletal muscle [2]. All are caused by mutations in the sodium channel gene SCN4A 3, 4, 5, 6. Physiologic study of these mutations in vitro reveals abnormalities like those present in patient muscle and is leading toward understanding the pathophysiologic basis of these diseases at the level of channel function and membrane

Other paroxysmal disorders are seen in humans

Among disorders of the nervous system, a large number of conditions exist in which seemingly normal people experience acute onset of transient neurological symptoms. Examples include the transient weakness seen in the periodic paralyses 2, 6, incoordination in the episodic ataxias [25], sudden falls in startle disease [26], headaches in migraineurs [27], and seizures in epileptic patients [28].

In addition to the shared feature of episodic occurrence among these disorders other similarities are

Similarities among paroxysmal disorders

All of these disorders have the shared feature of episodic occurrence. Other similarities include the factors that precipitate attacks in patients. For example, caffeine, chocolate, large carbohydrate meals, rest after exercise, and alterations in potassium (increases in some cases and decreases in others), precipitate paroxysmal events in subsets of the above-mentioned disorders.

Other recognized ion channel mutations in paroxysmal disease

Genetic linkage analysis, together with testing of candidate genes and positional cloning, led to the identification of three distinct voltage-gated ion channels (one sodium channel gene, SCN5A, and two potassium channel genes, HERG and KVLQT1) that, when mutant, can give rise to this syndrome 47, 48, 49.

The gene causing one form of inherited partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, was mapped to chromosome 20q13 in a large Australian family. Subsequently, a

Acknowledgements

The author is grateful to Drs. Jong Rho and Kevin Flanigan for helpful discussions and critical reading of the manuscript. Investigations in the laboratory are supported by NIH grant NS32711, by the H.A. Benning Endowment, by a grant from the Muscular Dystrophy Association, and by the Charles E. Culpeper Foundation. Dr. Ptáček is a Charles E. Culpeper Foundation Scholar.

References (56)

  • Koenig M, et al. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of...
  • Ptáček LJ, Johnson KJ, Griggs RC. Genetics and physiology of the myotonic muscle disorders. N Engl J Med...
  • Ptáček LJ, George AL, Griggs RC, Tawil R, Kallen RG, Barchi RL, Robertson M, Leppert M. Identification of a mutation in...
  • Rojas CV, et al. A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic...
  • McClatchey AI, et al. Temperature-sensitive mutations in the III–IV cytoplasmic loop region of the skeletal muscle...
  • Ptáček LJ, et al. Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita....
  • Cannon SC, Strittmatter SM. Functional expression of sodium channel mutations identified in families with periodic...
  • Cummins TR, et al. Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis. Neuron...
  • Chahine M, et al. Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. Neuron...
  • Yang N, et al. Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro. Proc...
  • Mitrovic N, et al. K(+)-aggravated myotonia: destabilization of the inactivated state of the human muscle Na+ channel...
  • Ptáček LJ, et al. Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell...
  • Jurkat Rott K, et al. A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet...
  • Elbaz A, et al. Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype...
  • Fouad G, et al. Genotype-phenotype correlations of DHP receptor alpha-1 gene mutations causing hypokalemic periodic...
  • Abdalla JA, et al. Linkage of Thomsen disease to the T-cell-receptor beta (TCRB) locus on chromosome 7q35. Am J Hum...
  • Koch MC, et al. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science...
  • George AL Jr, Crackower MA, Abdalla JA, Hudson AJ, Ebers GC. Molecular basis of Thomsen's disease (autosomal dominant...
  • Heine R, et al. Proof of a non-functional muscle chloride channel in recessive myotonia congenita (Becker) by detection...
  • Gronemeier M, et al. Nonsense and missense mutations in the muscular chloride channel gene Clc-1 of myotonic mice. J...
  • Zhang J, et al. Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and...
  • Pusch M, Steinmeyer K, Koch MC, Jentsch TJ. Mutations in dominant human myotonia congenita drastically alter the...
  • Fahlke C, Rosenbohm A, Mitrovic N, George AL Jr, Rudel R. Mechanism of voltage-dependent gating in skeletal muscle...
  • Fahlke C, Rudel R, Mitrovic N, Zhou M, George AL Jr. An aspartic acid residue important for voltage-dependent gating of...
  • Browne DL, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel...
  • Shiang R, et al. Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic...
  • Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for...
  • Commission on the Classification and Terminology of the International League against Epilepsy. Proposal for revised...
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