論文 - 詳細
| RRC ID | 44422 |
|---|---|
| 著者 | 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. |
| タイトル | A human Dravet syndrome model from patient induced pluripotent stem cells. |
| ジャーナル | 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. |
| 巻・号 | 6 |
| ページ | 19 |
| 公開日 | 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 |
| 引用数 | 57 |
| WOS 分野 | NEUROSCIENCES |
| リソース情報 | |
| ヒト・動物細胞 | |