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