Human skeletal muscle sodium channelopathies

  title={Human skeletal muscle sodium channelopathies},
  author={S Vicart and Damien Sternberg and Bertrand Fontaine and Giovanni Meola},
  journal={Neurological Sciences},
Ion channels are transmembrane proteins that allow ions to flow in or out of the cell. Sodium and potassium channel activation and inactivation are the basis of action potential’s production and conduction. During the past 15 years, ion channels have been implicated in diseases that have come to be known as the channelopathies. Over 30 mutations of the muscle channel gene SCN4A, which encodes the muscle voltage-gated sodium channel, have been described and associated with neuromuscular… 

Voltage-gated sodium channels: mutations, channelopathies and targets.

This review discusses aspects of voltage-gated sodium channel genes with an emphasis on cardiac muscle sodium channels, and explains commonalities and differences among the channel subtypes, the channelopathies caused by the sodium channel gene mutation and the specificity of toxins and blockers of theChannel subtypes.

Molecular Genetics of Skeletal Muscle Channelopathies

The skeletal muscle channelopathies are disorders of muscle excitability due to disruption of the normal functioning of skeletal muscle ion channels resulting in a number of disorders classified as periodic paralysis and nondystrophic myotonias.

Changes of Resurgent Na+ Currents in the Nav1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia

Findings suggest that the p.V445M mutation in the Nav1.4 channel results in an increase of both sustained and resurgent Na+ currents, which may contribute to hyperexcitability with repetitive firing and is likely to facilitate recurrent myotonia in SCM patients.

Genetic and molecular studies of skeletal muscle channelopathies

Two SCN4A mutations identified in this thesis were studied in vitro using twoelectrode voltage clamp and patch clamp in Xenopus laevis oocytes and HEK-293 cells, respectively and support the notion that D1420G is a pathogenic mutation.

A clinical and genetic study of the skeletal muscle channelopathies

The first cases of large scale rearrangements in CLCN1 causing myotonia congenita are described and the genetic diagnosis rate can be improved, and two cases that may be explained by variations in RYR1 are illustrated.

Recent Advances in the Pathogenesis and Drug Action in Periodic Paralyses and Related Channelopathies

It is now known that the fiber depolarization in the hypoPP is due to an unbalance between the novel identified depolarizing gating pore currents (Igp) carried by protons or Na+ ions flowing through aberrant alternative pathways of the mutant subunits and repolarizing inwardly rectifying potassium channel (Kir) currents which also includes the ATP-sensitive subtype.

Skeletal Muscle Na+ Channel Disorders

Five inherited human disorders affecting skeletal muscle contraction have been traced to mutations in the gene encoding the voltage-gated sodium channel Nav1.4, and the importance of understanding the role of the sodium channel in skeletal muscle function and disease state grows.

Sodium Channel Myotonia Due to Novel Mutations in Domain I of Nav1.4

Seven families with a series of symptoms ranging from asymptomatic to clearly myotonic signs that have in common two novel mutations, p.Ile215Thr and p.Gly241Val, in the first domain of the Nav1.4 channel are described and the first homozygous patient with sodium channel myotonia is presented.

Homozygosity for dominant mutations increases severity of muscle channelopathies

The first cases of homozygous patients for sodium channel mutations responsible for paramyotonia congenita or hypokalemic periodic paralysis are reported, suggesting that the severity of muscle channelopathies depends both on the degree of channel impairment caused by the mutation and on the number of mutant channels engaged in the pathophysiological process.

Skeletal muscle channelopathies: new insights into the periodic paralyses and nondystrophic myotonias

Advances in understanding of the clinical phenotypes, genetics, and molecular pathophysiology of the periodic paralyses, the nondystrophic myotonias, and other muscle channelopathies are summarized.



The Human Skeletal Muscle Na Channel Mutation R669H Associated with Hypokalemic Periodic Paralysis Enhances Slow Inactivation

It is demonstrated that, in R669H-associated HypoPP, enhanced slow inactivation does not preclude, and may contribute to, prolonged attacks of weakness and add support to previous evidence implicating the IIS4 voltage sensor in slow-inactivation gating.

Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro.

  • N. YangS. Ji A. George
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1994
Findings help to explain the phenotypic differences between HYPP and PC at the molecular and biophysical level and contribute to the understanding of Na+ channel structure and function.

Genotype-phenotype correlations in human skeletal muscle sodium channel diseases.

Further study of the genotype-phenotype correlations should not only increase the understanding of the variability of signs in this group of diseases, but could also provide a deeper insight in the function of the various regions of the sodium channel protein.

Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III‐IV linker.

Electrophysiological and molecular genetic studies strongly suggest that three dominant point mutations discovered at the same nucleotide position of the SCN4A gene encoding the adult skeletal muscle Na+ channel alpha‐subunit cause myotonia.

Activation and Inactivation of the Voltage-Gated Sodium Channel: Role of Segment S5 Revealed by a Novel Hyperkalaemic Periodic Paralysis Mutation

Results, showing that the I1495F and T704M hyperkalaemic periodic paralysis mutations both have profound effects on channel activation and fast–slow inactivation, suggest that the S5 segment maybe in a location where fast and slow inactivation converge.

A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation.

One allele with two novel mutations occurring simultaneously in the SCN4A gene, encoding the human skeletal muscle voltage-gated Na(+) channel, is identified, demonstrating that manifestation of HyperKPP does not necessarily require disruption of slow inactivation.

Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current.

The results prove that SCN4A, the gene encoding the sodium channel alpha subunit of skeletal muscle is responsible for HypoPP-2, a disease caused by enhanced channel inactivation and current reduction showing no myotonia.

Diseases caused by voltage-gated ion channels.

Defective slow inactivation of sodium channels contributes to familial periodic paralysis

SI is defective in a subset of mutant Na channels associated with episodic weakness (HyperPP or PMC) but remains intact for mutants studied so far that cause myotonia without weakness (PAM).

Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalaemic periodic paralysis type II.

The gating of both histidine mutants (Arg669His, Arg672His) can be modulated by changes of extra- or intracellular pH, suggesting that the decrease of pH in muscle cells might lead to an auto-compensation of functional defects.