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

Hyun Woo Kim, Zhejiu Quan, Young Beom Kim, Eunji Cheong, HeungDong Kim, Minjung Cho, Jiho Jang, Young Rang Yoo, Joon Soo Lee, Ji Hun Kim, Yang In Kim, Dae Sung Kim, hoonchul kang

Research output: Contribution to journalArticle

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 (>60 pA) 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.

Original languageEnglish
Pages (from-to)287-298
Number of pages12
JournalBrain and Development
Volume40
Issue number4
DOIs
Publication statusPublished - 2018 Apr 1

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Myoclonic Epilepsy
GABAergic Neurons
Sodium
Mutation
Nucleic Acid Databases
Induced Pluripotent Stem Cells
Frameshift Mutation
Nonsense Codon
Missense Mutation
Prosencephalon
Action Potentials
Seizures
Tissue Donors
Neurons
Injections

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Developmental Neuroscience
  • Clinical Neurology

Cite this

Kim, Hyun Woo ; Quan, Zhejiu ; Kim, Young Beom ; Cheong, Eunji ; Kim, HeungDong ; Cho, Minjung ; Jang, Jiho ; Yoo, Young Rang ; Lee, Joon Soo ; Kim, Ji Hun ; Kim, Yang In ; Kim, Dae Sung ; kang, hoonchul. / Differential effects on sodium current impairments by distinct SCN1A mutations in GABAergic neurons derived from Dravet syndrome patients. In: Brain and Development. 2018 ; Vol. 40, No. 4. pp. 287-298.
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Differential effects on sodium current impairments by distinct SCN1A mutations in GABAergic neurons derived from Dravet syndrome patients. / Kim, Hyun Woo; Quan, Zhejiu; Kim, Young Beom; Cheong, Eunji; Kim, HeungDong; Cho, Minjung; Jang, Jiho; Yoo, Young Rang; Lee, Joon Soo; Kim, Ji Hun; Kim, Yang In; Kim, Dae Sung; kang, hoonchul.

In: Brain and Development, Vol. 40, No. 4, 01.04.2018, p. 287-298.

Research output: Contribution to journalArticle

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AU - Kim, Hyun Woo

AU - Quan, Zhejiu

AU - Kim, Young Beom

AU - Cheong, Eunji

AU - Kim, HeungDong

AU - Cho, Minjung

AU - Jang, Jiho

AU - Yoo, Young Rang

AU - Lee, Joon Soo

AU - Kim, Ji Hun

AU - Kim, Yang In

AU - Kim, Dae Sung

AU - kang, hoonchul

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AB - 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 (>60 pA) 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.

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