RRC ID 44422
Author Higurashi N, Uchida T, Lossin C, Misumi Y, Okada Y, Akamatsu W, Imaizumi Y, Zhang B, Nabeshima K, Mori MX, Katsurabayashi S, Shirasaka Y, Okano H, Hirose S.
Title A human Dravet syndrome model from patient induced pluripotent stem cells.
Journal Mol Brain
Abstract BACKGROUND:Dravet syndrome is a devastating infantile-onset epilepsy syndrome with cognitive deficits and autistic traits caused by genetic alterations in SCN1A gene encoding the α-subunit of the voltage-gated sodium channel Na(v)1.1. Disease modeling using patient-derived induced pluripotent stem cells (iPSCs) can be a powerful tool to reproduce this syndrome's human pathology. However, no such effort has been reported to date. We here report a cellular model for DS that utilizes patient-derived iPSCs.
RESULTS:We generated iPSCs from a Dravet syndrome patient with a c.4933C>T substitution in SCN1A, which is predicted to result in truncation in the fourth homologous domain of the protein (p.R1645*). Neurons derived from these iPSCs were primarily GABAergic (>50%), although glutamatergic neurons were observed as a minor population (<1%). Current-clamp analyses revealed significant impairment in action potential generation when strong depolarizing currents were injected.
CONCLUSIONS:Our results indicate a functional decline in Dravet neurons, especially in the GABAergic subtype, which supports previous findings in murine disease models, where loss-of-function in GABAergic inhibition appears to be a main driver in epileptogenesis. Our data indicate that patient-derived iPSCs may serve as a new and powerful research platform for genetic disorders, including the epilepsies.
Volume 6
Pages 19
Published 2013-5-2
DOI 10.1186/1756-6606-6-19
PII 1756-6606-6-19
PMID 23639079
PMC PMC3655893
MeSH Action Potentials Adult Cell Differentiation Epilepsies, Myoclonic / pathology* Epilepsies, Myoclonic / physiopathology Female Genes, Reporter / genetics Humans Induced Pluripotent Stem Cells / metabolism Induced Pluripotent Stem Cells / pathology* Infant Lentivirus / metabolism Models, Biological* NAV1.1 Voltage-Gated Sodium Channel / metabolism Neurons / metabolism Neurons / pathology Parvalbumins / genetics Parvalbumins / metabolism RNA, Messenger / genetics RNA, Messenger / metabolism Real-Time Polymerase Chain Reaction Young Adult
IF 4.686
Times Cited 57
Human and Animal Cells