Myasthenic syndrome caused by mutation of the SCN4A sodium channel

Akira Tsujino, Chantal Maertenst, Kinji Ohno, Xin Ming Shen, Taku Fukuda, C. Michael Harper, Stephen C. Cannon, Andrew G. Engel

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

In a myasthenic syndrome associated with fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth, nerve stimulation at physiologic rates rapidly decremented the compound muscle action potential. Intercostal muscle studies revealed no abnormality of the resting membrane potential, evoked quantal release, synaptic potentials, acetylcholine receptor channel kinetics, or endplate ultrastructure, but endplate potentials depolarizing the resting potential to -40 mV failed to excite action potentials. Pursuing this clue, we sequenced SCN4A encoding the skeletal muscle sodium channel (Nav1.4) and detected two heteroallelic mutations involving conserved residues not present in 400 normal alleles: S246L in the S4/S5 cytoplasmic linker in domain I, and V1442E in the S3/S4 extracellular linker in domain IV. The genetically engineered V1442E-Na channel expressed in HEK cells shows marked enhancement of fast inactivation close to the resting potential, and enhanced use-dependent inactivation on high-frequency stimulation; S246L is likely a benign polymorphism. The V1442E mutation in SCN4A defines a novel disease mechanism and a novel phenotype with myasthenic features.

Original languageEnglish (US)
Pages (from-to)7377-7382
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number12
DOIs
StatePublished - Jun 10 2003

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Sodium Channels
Muscle Weakness
Membrane Potentials
Mutation
Action Potentials
Progressive Bulbar Palsy
Respiratory Paralysis
Intercostal Muscles
Synaptic Potentials
Cholinergic Receptors
Skeletal Muscle
Alleles
Parturition
Phenotype
Muscles

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Tsujino, A., Maertenst, C., Ohno, K., Shen, X. M., Fukuda, T., Harper, C. M., ... Engel, A. G. (2003). Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proceedings of the National Academy of Sciences of the United States of America, 100(12), 7377-7382. https://doi.org/10.1073/pnas.1230273100

Myasthenic syndrome caused by mutation of the SCN4A sodium channel. / Tsujino, Akira; Maertenst, Chantal; Ohno, Kinji; Shen, Xin Ming; Fukuda, Taku; Harper, C. Michael; Cannon, Stephen C.; Engel, Andrew G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 12, 10.06.2003, p. 7377-7382.

Research output: Contribution to journalArticle

Tsujino, A, Maertenst, C, Ohno, K, Shen, XM, Fukuda, T, Harper, CM, Cannon, SC & Engel, AG 2003, 'Myasthenic syndrome caused by mutation of the SCN4A sodium channel', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 12, pp. 7377-7382. https://doi.org/10.1073/pnas.1230273100
Tsujino, Akira ; Maertenst, Chantal ; Ohno, Kinji ; Shen, Xin Ming ; Fukuda, Taku ; Harper, C. Michael ; Cannon, Stephen C. ; Engel, Andrew G. / Myasthenic syndrome caused by mutation of the SCN4A sodium channel. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 12. pp. 7377-7382.
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