Publication
Title
A functional null mutation of **SCN1B** in a patient with Dravet syndrome
Author
Abstract
Dravet syndrome (also called severe myoclonic epilepsy of infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations in SCN1A, encoding voltage-gated sodium channel Nav1.1 subunits. Sodium channels are modulated by â1 subunits, encoded by SCN1B, a gene also linked to epilepsy. Here we report the first patient with Dravet syndrome associated with a recessive mutation in SCN1B (p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little to no cell surface expression despite normal total cellular expression. This occurred regardless of coexpression of Nav1.1 subunits. Because the patient was homozygous for the mutation, these data suggest a functional SCN1B null phenotype. To understand the consequences of the lack of â1 cell surface expression in vivo, hippocampal slice recordings were performed in Scn1b/ versus Scn1b+/+ mice. Scn1b/ CA3 neurons fired evoked action potentials with a significantly higher peak voltage and significantly greater amplitude compared with wild type. However, in contrast to the Scn1a+/ model of Dravet syndrome, we found no measurable differences in sodium current density in acutely dissociated CA3 hippocampal neurons. Whereas Scn1b/ mice seize spontaneously, the seizure susceptibility of Scn1b+/ mice was similar to wild type, suggesting that, like the parents of this patient, one functional SCN1B allele is sufficient for normal control of electrical excitability. We conclude that SCN1B p.R125C is an autosomal recessive cause of Dravet syndrome through functional gene inactivation.
Language
English
Source (journal)
The journal of neuroscience. - Baltimore, Md
Publication
Baltimore, Md : 2009
ISSN
0270-6474 [Print]
1529-2401 [Online]
Volume/pages
29:34(2009), p. 10764-10778
ISI
000269317900029
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 12.10.2009
Last edited 17.09.2017
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