A human Dravet syndrome model from patient induced pluripotent stem cells

Norimichi Higurashi, Taku Uchida, Christoph Lossin, Yoshio Misumi, Yohei Okada, Wado Akamatsu, Yoichi Imaizumi, Bo Zhang, Kazuki Nabeshima, Masayuki X. Mori, Shutaro Katsurabayashi, Yukiyoshi Shirasaka, Hideyuki Okano, Shinichi Hirose

研究成果: Article査読

76 被引用数 (Scopus)

抄録

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 Nav1.1. 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.

本文言語English
論文番号19
ジャーナルMolecular brain
6
1
DOI
出版ステータスPublished - 2013

ASJC Scopus subject areas

  • 分子生物学
  • 細胞および分子神経科学

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