Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel

  title={Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel},
  author={Andrea I. McClatchey and Diane M. McKenna-Yasek and Didier P. Cros and Hilary G. Worthen and Ralph W. Kuncl and Shari DeSilva and David R. Cornblath and James F. Gusella and Robert H. Brown},
  journal={Nature Genetics},
Mutations in the skeletal muscle sodium channel gene (SCN4A) have been described in paramyotonia congenita (PMC) and hyperkalaemic periodic paralysis (HPP). We have found two mutations in SCN4A which affect regions of the sodium channel not previously associated with a disease phenotype. Furthermore, affected family members display an unusual mixture of clinical features reminiscent of PMC, HPP and of a third disorder, myotonia congenita (MC). The highly variable individual expression of these… 

A novel muscle sodium channel mutation causes painful congenital myotonia

A novel SCN4A mutation causing the replacement of Val445 in the sixth transmembrane segment of domain 1 with methionine was discovered in all affected individuals and is the likely genetic basis for the syndrome.

Lack of sodium channel mutation in an Italian family with paramyotonia congenita.

The existence of a second gene different from SCN4A that can give rise to a clinical PC phenotype can be speculated upon.

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.

Mutation in the S4 segment of the adult skeletal sodium channel gene in an Italian Paramyotonia Congenita (PC) family

A mutation in an S4 segment of the adult skeletal muscle sodium channel in a clinically-defined Italian family is described that leads to the paramyotonia congenita (PC) phenotype with dominant autosomal inheritance and temperature-related symptoms (regional weakness following cooling and exercise), present since childhood in all of the affected family members.

Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1

Mutation analysis of the KCNA1 coding region in families identified four different missense point mutations present in the heterozygous state, indicating that EA/myokymia can result from mutations in this gene.

Disorders of Skeletal Muscle Membrane Excitability: Myotonia Congenita, Paramyotonia Congenita, Periodic Paralysis, and Related Syndromes

This chapter reviews the disorders of skeletal muscle membrane excitability resulting from ion channel dysfunction, as well as related disorders.

A novel mutation in the gene for the adult skeletal muscle sodium channel alpha-subunit (SCN4A) that causes paramyotonia congenita of von Eulenburg.

4 mutations that cause a decrease in positive charge in the S4/D4 are associated with the phenotype of PMC of von Eulenburg, providing an important genotype-phenotype correlation in sodium channelopathies.

Mutations in the Muscle Sodium Channel Gene (SCN4A) in 13 French Families with Hyperkalemic Periodic Paralysis and Paramyotonia Congenita: Phenotype to Genotype Correlations and Demonstration of the Predominance of Two Mutations

Recurrent mutations of SCN4A may contribute to the predominance of these two mutations in the French population by contributing to the severity of myotonia and its permanence were variable.



Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene.

Parts of the adult muscle sodium channel alpha-subunit gene were cloned and mapped near the human growth hormone locus (GH1) on chromosome 17 and showed tight linkage to the genetic defect with no recombinants detected.

Paramyotonia congenita and hyperkalemic periodic paralysis are linked to the adult muscle sodium channel gene

The hypothesis that hyperkalemic periodic paralysis (without myotonia) and paramyotonia congenita are tightly linked to the tetrodotoxin‐sensitive adult skeletal muscle sodium channel gene on chromosome 17q23‐25 in two large pedigrees is tested.

Analysis in a large hyperkalemic periodic paralysis pedigree supports tight linkage to a sodium channel locus.

Close genetic linkage between an NaCh gene and the HYPP locus in another family is demonstrated and the absence of any obligate recombinations in the two families strengthens the argument that this Na Ch gene is the site of the defect in this disorder.

Linkage of atypical myotonia congenita to a sodium channel locus

The molecular alteration causing acetazolamide-responsive myotonia congenita is likely an allelic defect in this human, skeletal-muscle, sodium channel gene.

Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium-channel gene locus.

Linkage results implicate a sodium-channel gene as an important candidate for the site of mutation responsible for PC, and provide strong evidence for the hypothesis that PC and HYPP are allelic disorders.

Confirmation of linkage of hyperkalaemic periodic paralysis to chromosome 17.

Linkage studies were performed in six European families with hyperkalaemic periodic paralysis with myotonia, suggesting that the disease is caused by dominant mutations of the adult sodium channel, and that it is probably a genetically homogeneous disorder.

A Met-to-Val mutation in the skeletal muscle Na+ channel α-subunit in hyperkalaemic periodic paralysis

An A - G substitution in the patient's messenger RNA that causes a Met-Val change in a highly conserved region of the α-subunit, predicted to be in a transmembrane domain is identified and discovered a voltage-gated channel mutation responsible for a human genetic disease.