Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome

W. David Arnold, Daniel H. Feldman, Sandra Ramirez, Liuyuan He, Darine Kassar, Adam Quick, Tara L. Klassen, Marian Lara, Joanna Nguyen, John T. Kissel, Christoph Lossin, Ricardo A Maselli

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Objective To describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology. Methods We used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Nav1.4. Results Clinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Nav1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel's voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics. Interpretation We conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient's muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel's involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function. Ann Neurol 2015;77:840-850

Original languageEnglish (US)
Pages (from-to)840-850
Number of pages11
JournalAnnals of Neurology
Volume77
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

Congenital Myasthenic Syndromes
Sodium Channels
Muscles
Hyperkalemic Periodic Paralysis
Myotonic Disorders
Genes
Phenotype
Muscular Diseases
Histidine
Constriction
Arginine
Skeletal Muscle
Mutation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Medicine(all)

Cite this

Arnold, W. D., Feldman, D. H., Ramirez, S., He, L., Kassar, D., Quick, A., ... Maselli, R. A. (2015). Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome. Annals of Neurology, 77(5), 840-850. https://doi.org/10.1002/ana.24389

Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome. / Arnold, W. David; Feldman, Daniel H.; Ramirez, Sandra; He, Liuyuan; Kassar, Darine; Quick, Adam; Klassen, Tara L.; Lara, Marian; Nguyen, Joanna; Kissel, John T.; Lossin, Christoph; Maselli, Ricardo A.

In: Annals of Neurology, Vol. 77, No. 5, 01.05.2015, p. 840-850.

Research output: Contribution to journalArticle

Arnold, WD, Feldman, DH, Ramirez, S, He, L, Kassar, D, Quick, A, Klassen, TL, Lara, M, Nguyen, J, Kissel, JT, Lossin, C & Maselli, RA 2015, 'Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome', Annals of Neurology, vol. 77, no. 5, pp. 840-850. https://doi.org/10.1002/ana.24389
Arnold WD, Feldman DH, Ramirez S, He L, Kassar D, Quick A et al. Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome. Annals of Neurology. 2015 May 1;77(5):840-850. https://doi.org/10.1002/ana.24389
Arnold, W. David ; Feldman, Daniel H. ; Ramirez, Sandra ; He, Liuyuan ; Kassar, Darine ; Quick, Adam ; Klassen, Tara L. ; Lara, Marian ; Nguyen, Joanna ; Kissel, John T. ; Lossin, Christoph ; Maselli, Ricardo A. / Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome. In: Annals of Neurology. 2015 ; Vol. 77, No. 5. pp. 840-850.
@article{feacfec6cd954eb3bbba5e76ade66d55,
title = "Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome",
abstract = "Objective To describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology. Methods We used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Nav1.4. Results Clinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Nav1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel's voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics. Interpretation We conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient's muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel's involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function. Ann Neurol 2015;77:840-850",
author = "Arnold, {W. David} and Feldman, {Daniel H.} and Sandra Ramirez and Liuyuan He and Darine Kassar and Adam Quick and Klassen, {Tara L.} and Marian Lara and Joanna Nguyen and Kissel, {John T.} and Christoph Lossin and Maselli, {Ricardo A}",
year = "2015",
month = "5",
day = "1",
doi = "10.1002/ana.24389",
language = "English (US)",
volume = "77",
pages = "840--850",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "5",

}

TY - JOUR

T1 - Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome

AU - Arnold, W. David

AU - Feldman, Daniel H.

AU - Ramirez, Sandra

AU - He, Liuyuan

AU - Kassar, Darine

AU - Quick, Adam

AU - Klassen, Tara L.

AU - Lara, Marian

AU - Nguyen, Joanna

AU - Kissel, John T.

AU - Lossin, Christoph

AU - Maselli, Ricardo A

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Objective To describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology. Methods We used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Nav1.4. Results Clinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Nav1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel's voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics. Interpretation We conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient's muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel's involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function. Ann Neurol 2015;77:840-850

AB - Objective To describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology. Methods We used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Nav1.4. Results Clinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Nav1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel's voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics. Interpretation We conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient's muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel's involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function. Ann Neurol 2015;77:840-850

UR - http://www.scopus.com/inward/record.url?scp=84928138708&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928138708&partnerID=8YFLogxK

U2 - 10.1002/ana.24389

DO - 10.1002/ana.24389

M3 - Article

C2 - 25707578

AN - SCOPUS:84928138708

VL - 77

SP - 840

EP - 850

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 5

ER -