Reference - Detail
|Author||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.|
|Title||A human Dravet syndrome model from patient induced pluripotent stem cells.|
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.
|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|
|Human and Animal Cells|