A Functional Null Mutation of SCN1B in a Patient with Dravet Syndrome

作者：Patino Gustavo A; Claes Lieve R F; Lopez Santiago Luis F; Slat Emily A; Dondeti Raja S R; Chen Chunling; O'Malley Heather A; Gray Charles B B; Miyazaki Haruko; Nukina Nobuyuki; Oyama Fumitaka; De Jonghe Peter; Isom Lori L^*

来源：Journal of Neuroscience, 2009, 29(34): 10764-10778.

DOI：10.1523/JNEUROSCI.2475-09.2009

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 Na(v)1.1 alpha subunits. Sodium channels are modulated by beta 1 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 Na(v)1.1 alpha 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 beta 1 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.

• 出版日期2009-8-26