title: Establishment of isogenic iPSCs from an individual with SCN1A mutation mosaicism as a model for investigating neurocognitive impairment in Dravet syndrome.
abstract: Dravet syndrome (DS) is a severe childhood epilepsy typically caused by de novo dominant mutations in SCN1A. Although patients with DS frequently have neurocognitive abnormalities, the precise neural mechanisms responsible for their expression have not been elucidated. There are wide phenotypic differences among individuals with SCN1A mutations, suggesting that factors other than the SCN1A mutation modify the phenotype. Therefore, a well-controlled cellular model system is required to improve our understanding of the mechanisms underlying DS. Here we generated induced pluripotent stem cell (iPSC) lines from an individual with SCN1A mutation mosaicism, and separately cloned iPSC lines both with and without the SCN1A mutation. These clones theoretically have the same genetic backgrounds, except for the SCN1A gene, and should serve as an ideal pair for investigating the pathophysiology caused by SCN1A mutations. Quantitative reverse transcription-PCR and western blot analysis revealed higher tyrosine hydroxylase mRNA and protein expression levels in mutant neurons than in wild-type neurons. Moreover, dopamine concentrations in media collected from mutant neural cultures were higher than those from wild-type neural cultures. Our findings suggest that SCN1A mutation leads to changes in the dopamine system that may contribute to the behavioral abnormalities in DS.
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Hiroshi
authors: H
authors: Maeda
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Tomohiro
authors: T
authors: Chiyonobu
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.|Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors: Michiko
authors: M
authors: Yoshida
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Satoshi
authors: S
authors: Yamashita
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Masashi
authors: M
authors: Zuiki
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Satoshi
authors: S
authors: Kidowaki
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.|Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors: Kenichi
authors: K
authors: Isoda
authors: Laboratory for Neurogenetics, RIKEN Brain Science Institute, Saitama, Japan.
authors: Kazuhiro
authors: K
authors: Yamakawa
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Masafumi
authors: M
authors: Morimoto
authors: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors: Tatsutoshi
authors: T
authors: Nakahata
authors: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors: Megumu K
authors: MK
authors: Saito
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Hajime
authors: H
authors: Hosoi
mesh_terms: D002454:Cell Differentiation; D060825:Cognitive Dysfunction / Q000235:genetics*; D004252:DNA Mutational Analysis; D004298:Dopamine / Q000378:metabolism; D004831:Epilepsies, Myoclonic / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D056726:Genetic Association Studies; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D059785:Karyotype; D008297:Male; D009030:Mosaicism; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010375:Pedigree; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine