A sodium channel mutation causing epilepsy in man exhibits subtle defects in fast inactivation and activation in vitro

Alexi K. Alekov, Masmudur Rahman, Nenad Mitrovic, Frank Lehmannhorn, Holger Lerche

Research output: Contribution to journalArticle

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Abstract

1. Generalized epilepsy with febrile seizures plus (GEFS+) is a benign epileptic syndrome of humans. It is characterized by febrile and afebrile generalized seizures that occur predominantly in childhood and respond well to standard antiepileptic therapy. A mutation in the β1-subunit of the voltage-gated sodium channel, linked to chromosome 19q13 (GEFS+ type 1) has been found in one family. For four other families, linkage was found to chromosome 2q21-33 (GEFS+ type 2) where three genes encoding neuronal sodium channel α-subunits are located (SCN1-3A). Recently, the first two mutations were identified in SCN1A. 2. We introduced one of these mutations, which is highly conserved to SCN1A, into the cDNA of the gene SCN4A encoding the α-subunit of the human skeletal muscle sodium channel (hSkm1). The mutation is located in the S4 voltage sensor of domain IV, predicting substitution of histidine for the fifth of eight arginines (R1460H in hSkm1). Functional studies were performed by expressing the α-subunit alone in the mammalian tsA201 cell line using the whole-cell patch clamp technique. 3. Compared to wild-type (WT), mutant R1460H channels showed small defects in fast inactivation. The time course of inactivation was slightly (1.5-fold) slowed and its voltage dependence reduced, and recovery from inactivation was accelerated 3-fold. However, there was no increase in persistent sodium current as observed for SCN4A mutations causing myotonia or periodic paralysis. The activation time course of R1460H channels was slightly accelerated. Slow inactivation was slightly but significantly stabilized, confirming the importance of this region for slow inactivation. 4. The combination of activation and fast inactivation defects can explain the occurrence of epileptic seizures, but the effects were much more subtle than the inactivation defects described previously for mutations in SCN4A causing disease in skeletal muscle. Hence, with regard to pathological excitability, our results suggest a greater vulnerability of the central nervous system compared to muscle tissue.

Original languageEnglish (US)
Pages (from-to)533-539
Number of pages7
JournalJournal of Physiology
Volume529
Issue number3
DOIs
StatePublished - Dec 15 2000
Externally publishedYes

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Sodium Channels
Epilepsy
Mutation
Skeletal Muscle
Chromosomes
Myotonia
Voltage-Gated Sodium Channels
Patch-Clamp Techniques
Histidine
Paralysis
Anticonvulsants
Genes
Arginine
In Vitro Techniques
Seizures
Fever
Central Nervous System
Complementary DNA
Sodium
Cell Line

ASJC Scopus subject areas

  • Physiology

Cite this

A sodium channel mutation causing epilepsy in man exhibits subtle defects in fast inactivation and activation in vitro. / Alekov, Alexi K.; Rahman, Masmudur; Mitrovic, Nenad; Lehmannhorn, Frank; Lerche, Holger.

In: Journal of Physiology, Vol. 529, No. 3, 15.12.2000, p. 533-539.

Research output: Contribution to journalArticle

Alekov, Alexi K. ; Rahman, Masmudur ; Mitrovic, Nenad ; Lehmannhorn, Frank ; Lerche, Holger. / A sodium channel mutation causing epilepsy in man exhibits subtle defects in fast inactivation and activation in vitro. In: Journal of Physiology. 2000 ; Vol. 529, No. 3. pp. 533-539.
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AU - Rahman, Masmudur

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AU - Lehmannhorn, Frank

AU - Lerche, Holger

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N2 - 1. Generalized epilepsy with febrile seizures plus (GEFS+) is a benign epileptic syndrome of humans. It is characterized by febrile and afebrile generalized seizures that occur predominantly in childhood and respond well to standard antiepileptic therapy. A mutation in the β1-subunit of the voltage-gated sodium channel, linked to chromosome 19q13 (GEFS+ type 1) has been found in one family. For four other families, linkage was found to chromosome 2q21-33 (GEFS+ type 2) where three genes encoding neuronal sodium channel α-subunits are located (SCN1-3A). Recently, the first two mutations were identified in SCN1A. 2. We introduced one of these mutations, which is highly conserved to SCN1A, into the cDNA of the gene SCN4A encoding the α-subunit of the human skeletal muscle sodium channel (hSkm1). The mutation is located in the S4 voltage sensor of domain IV, predicting substitution of histidine for the fifth of eight arginines (R1460H in hSkm1). Functional studies were performed by expressing the α-subunit alone in the mammalian tsA201 cell line using the whole-cell patch clamp technique. 3. Compared to wild-type (WT), mutant R1460H channels showed small defects in fast inactivation. The time course of inactivation was slightly (1.5-fold) slowed and its voltage dependence reduced, and recovery from inactivation was accelerated 3-fold. However, there was no increase in persistent sodium current as observed for SCN4A mutations causing myotonia or periodic paralysis. The activation time course of R1460H channels was slightly accelerated. Slow inactivation was slightly but significantly stabilized, confirming the importance of this region for slow inactivation. 4. The combination of activation and fast inactivation defects can explain the occurrence of epileptic seizures, but the effects were much more subtle than the inactivation defects described previously for mutations in SCN4A causing disease in skeletal muscle. Hence, with regard to pathological excitability, our results suggest a greater vulnerability of the central nervous system compared to muscle tissue.

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