Mice with an NaV1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis

Fenfen Wu, Wentao Mi, Yu Fu, Arie Struyk, Stephen C. Cannon

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Over 60 mutations of SCN4A encoding the NaV1.4 sodium channel of skeletal muscle have been identified in patients with myotonia, periodic paralysis, myasthenia, or congenital myopathy. Most mutations are missense with gain-of-function defects that cause susceptibility to myotonia or periodic paralysis. Loss-of-function from enhanced inactivation or null alleles is rare and has been associated with myasthenia and congenital myopathy, while a mix of loss and gain of function changes has an uncertain relation to hypokalaemic periodic paralysis. To better define the functional consequences for a loss-of-function, we generated NaV1.4 null mice by deletion of exon 12. Heterozygous null mice have latent myasthenia and a right shift of the forcestimulus relation, without evidence of periodic paralysis. Sodium current density was half that of wild-type muscle and no compensation by retained expression of the foetal NaV1.5 isoform was detected. Mice null for NaV1.4 did not survive beyond the second postnatal day. This mouse model shows remarkable preservation of muscle function and viability for haploinsufficiency of NaV1.4, as has been reported in humans, with a propensity for pseudo-myasthenia caused by a marginal Na+ current density to support sustained high-frequency action potentials in muscle.

Original languageEnglish (US)
Pages (from-to)1688-1699
Number of pages12
JournalBrain
Volume139
Issue number6
DOIs
StatePublished - 2016

Fingerprint

Sodium Channels
Paralysis
Alleles
Myotonia Congenita
Myotonia
Muscles
Hypokalemic Periodic Paralysis
Haploinsufficiency
Missense Mutation
Action Potentials
Exons
Protein Isoforms
Skeletal Muscle
Sodium
Mutation
Susceptibility
Mouse
Allele

Keywords

  • Channelopathy
  • Congenital myasthenic syndrome
  • SCN4A
  • Skeletal muscle
  • Weakness

ASJC Scopus subject areas

  • Medicine(all)
  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Mice with an NaV1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis. / Wu, Fenfen; Mi, Wentao; Fu, Yu; Struyk, Arie; Cannon, Stephen C.

In: Brain, Vol. 139, No. 6, 2016, p. 1688-1699.

Research output: Contribution to journalArticle

Wu, Fenfen ; Mi, Wentao ; Fu, Yu ; Struyk, Arie ; Cannon, Stephen C. / Mice with an NaV1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis. In: Brain. 2016 ; Vol. 139, No. 6. pp. 1688-1699.
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