title: A human Dravet syndrome model from patient induced pluripotent stem cells.
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.
authors: Department of Pediatrics, School of Medicine, Fukuoka University, 45-1, 7-chome, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors: Norimichi
authors: N
authors: Higurashi
authors: Taku
authors: T
authors: Uchida
authors: Christoph
authors: C
authors: Lossin
authors: Yoshio
authors: Y
authors: Misumi
authors: Yohei
authors: Y
authors: Okada
authors: Wado
authors: W
authors: Akamatsu
authors: Yoichi
authors: Y
authors: Imaizumi
authors: Bo
authors: B
authors: Zhang
authors: Kazuki
authors: K
authors: Nabeshima
authors: Masayuki X
authors: MX
authors: Mori
authors: Shutaro
authors: S
authors: Katsurabayashi
authors: Yukiyoshi
authors: Y
authors: Shirasaka
authors: Hideyuki
authors: H
authors: Okano
authors: Shinichi
authors: S
authors: Hirose
mesh_terms: D000200:Action Potentials; D000328:Adult; D002454:Cell Differentiation; D004831:Epilepsies, Myoclonic / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D007223:Infant; D016086:Lentivirus / Q000378:metabolism; D008954:Models, Biological; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D010320:Parvalbumins; D012333:RNA, Messenger
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