A Human Dravet Syndrome Model from Patient Induced Pluripotent Stem Cells

Overview

Journal Mol Brain

Publisher Biomed Central

Specialties Molecular Biology
Neurology

Date 2013 May 4

PMID 23639079

Citations 66

Authors

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

Affiliations

Soon will be listed here.

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.

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