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Differential effects on sodium current impairments by distinct SCN1A mutations in GABAergic neurons derived from Dravet syndrome patients

Authors
 Hyun Woo Kim  ;  Zhejiu Quan  ;  Young-Beom Kim  ;  Eunji Cheong  ;  Heung Dong Kim  ;  Minjung Cho  ;  Jiho Jang  ;  Young Rang Yoo  ;  Joon Soo Lee  ;  Ji Hun Kim  ;  Yang In Kim  ;  Dae-Sung Kim  ;  Hoon-Chul Kang 
Citation
 BRAIN & DEVELOPMENT, Vol.40(4) : 287-298, 2018 
Journal Title
BRAIN & DEVELOPMENT
ISSN
 0387-7604 
Issue Date
2018
Keywords
Dravet syndrome ; Induced pluripotent stem cell ; Voltage-gated sodium channel
Abstract
BACKGROUND: We investigated how two distinct mutations in SCN1A differentially affect electrophysiological properties of the patient-derived GABAergic neurons and clinical severities in two Dravet syndrome (DS) patients. MATERIALS AND METHODS: We established induced pluripotent stem cells from two DS patients with different mutations in SCN1A and subsequently differentiated them into forebrain GABAergic neurons. Functionality of differentiated GABAergic neurons was examined by electrophysiological recordings. RESULTS: DS-1 patient had a missense mutation, c.4261G>T [GenBank: NM_006920.4] and DS-2 patient had a nonsense frameshift mutation, c.3576_3580 del TCAAA [GenBank: NM_006920.4]. Clinically, contrary to our expectations, DS-1 patient had more severe symptoms including frequency of seizure episodes and the extent of intellectual ability penetration than DS-2 patient. Electrophysiologic recordings showed significantly lower sodium current density and reduced action potential frequency at strong current injection (>60pA) in GABAergic neurons derived from both. Intriguingly, unique genetic alterations of SCN1A differentially impacted electrophysiological impairment of the neurons, and the impairment's extent corresponded with the symptomatic severity of the donor from which the iPSCs were derived. CONCLUSION: Our results suggest the possibility that patient-derived iPSCs may provide a reliable in vitro system that reflects clinical severities in individuals with DS.
Full Text
https://www.sciencedirect.com/science/article/pii/S038776041730308X
DOI
10.1016/j.braindev.2017.12.002
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hoon Chul(강훈철) ORCID logo https://orcid.org/0000-0002-3659-8847
Kim, Heung Dong(김흥동) ORCID logo https://orcid.org/0000-0002-8031-7336
Lee, Joon Soo(이준수) ORCID logo https://orcid.org/0000-0001-9036-9343
Jang, Ji Ho(장지호) ORCID logo https://orcid.org/0000-0001-5551-3514
Cho, Min Jung(조민정)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/162099
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