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Mol Brain. 2013 May 2;6:19. doi: 10.1186/1756-6606-6-19.

A human Dravet syndrome model from patient induced pluripotent stem cells.

Author information

1
Department of Pediatrics, School of Medicine, Fukuoka University, 45-1, 7-chome, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.

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.

PMID:
23639079
PMCID:
PMC3655893
DOI:
10.1186/1756-6606-6-19
[Indexed for MEDLINE]
Free PMC Article
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