| A functional null mutation of SCN1B in a patient with Dravet syndrome. | |
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MedLine Citation:
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PMID: 19710327 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 beta1 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 beta1 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. |
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Authors:
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Gustavo A Patino; Lieve R F Claes; Luis F Lopez-Santiago; Emily A Slat; Raja S R Dondeti; Chunling Chen; Heather A O'Malley; Charles B B Gray; Haruko Miyazaki; Nobuyuki Nukina; Fumitaka Oyama; Peter De Jonghe; Lori L Isom |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 29 ISSN: 1529-2401 ISO Abbreviation: J. Neurosci. Publication Date: 2009 Aug |
Date Detail:
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Created Date: 2009-08-27 Completed Date: 2009-09-10 Revised Date: 2010-12-03 |
Medline Journal Info:
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Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: United States |
Other Details:
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Languages: eng Pagination: 10764-78 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Program in Neuroscience, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-5632, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arginine / genetics Biophysics Cell Line, Transformed Cysteine / genetics DNA Mutational Analysis Disease Models, Animal Electric Stimulation Epilepsies, Myoclonic / genetics*, mortality, physiopathology* Female Green Fluorescent Proteins / genetics Hippocampus / pathology Humans Infant Male Mice Mice, Inbred C57BL Mice, Knockout Models, Molecular Nerve Tissue Proteins / deficiency Oocytes Polymorphism, Single Nucleotide / genetics* Sodium Channels / deficiency, genetics* Temperature Transfection Twins Xenopus laevis |
| Grant Support | |
ID/Acronym/Agency:
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MH059980/MH/NIMH NIH HHS; R01 MH059980-08/MH/NIMH NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Nerve Tissue Proteins; 0/SCN1B protein, human; 0/Scn1b protein, mouse; 0/Sodium Channels; 0/enhanced green fluorescent protein; 0/sodium channel, voltage-gated, type I, alpha protein; 147336-22-9/Green Fluorescent Proteins; 52-90-4/Cysteine; 74-79-3/Arginine |
| Comments/Corrections | |
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