dc.contributor.author | Xie, Yunyao | |
dc.contributor.author | Ng, Nathan N. | |
dc.contributor.author | Safrina, Olga S. | |
dc.contributor.author | Ramos, Carmen M. | |
dc.contributor.author | Ess, Kevin C. | |
dc.contributor.author | Schwartz, Philip H. | |
dc.contributor.author | Smith, Martin A. | |
dc.contributor.author | O'Dowd, Diane K. | |
dc.date.accessioned | 2020-09-18T21:38:57Z | |
dc.date.available | 2020-09-18T21:38:57Z | |
dc.date.issued | 2020-02 | |
dc.identifier.citation | Yunyao Xie, Nathan N. Ng, Olga S. Safrina, Carmen M. Ramos, Kevin C. Ess, Philip H. Schwartz, Martin A. Smith, Diane K. O'Dowd, Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associated SCN1A mutation, Neurobiology of Disease, Volume 134, 2020, 104627, ISSN 0969-9961 | en_US |
dc.identifier.issn | 0969-9961 | |
dc.identifier.uri | http://hdl.handle.net/1803/15989 | |
dc.description.abstract | Over 1250 mutations in SCN1A, the Navl.1 voltage-gated sodium channel gene, are associated with seizure disorders including GEES +. To evaluate how a specific mutation, independent of genetic background, causes seizure activity we generated two pairs of isogenic human iPSC lines by CRISPR/Cas9 gene editing. One pair is a control line from an unaffected sibling, and the mutated control carrying the GEFS+ K1270T SCN1A mutation. The second pair is a GEFS+ patient line with the K1270T mutation, and the corrected patient line. By comparing the electrophysiological properties in inhibitory and excitatory iPSC-derived neurons from these pairs, we found the K1270T mutation causes cell type-specific alterations in sodium current density and evoked firing, resulting in hyperactive neural networks. We also identified differences associated with genetic background and interaction between the mutation and genetic background. Comparisons within and between dual pairs of isogenic iPSC-derived neuronal cultures provide a novel platform for evaluating cellular mechanisms underlying a disease phenotype and for developing patient-specific anti-seizure therapies. | en_US |
dc.description.sponsorship | This work was supported by the National Institutes of Health grants R01 NS083009 (D.K.O.), R01 GHD059967 grant (P.H.S.), and R01 NS078289 (K.C.E.) and a California Institute for Regenerative Medicine Bridges to Stem Cell Research grant CIRM-EDUC2-08383 (C.M.R.). We would also like to thank Alexander E. Stover for generating the iPSCs, Priscilla Figueroa, Noor Osman and Daniel R. Benavides for help on astroglial cultures, Sara E. Konopelski for help on screening of clones, Karla Soto Sauza for help on immunostaining and cell counting and Longwen Huang for input on the manuscript. | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | Neurobiology of Disease | en_US |
dc.rights | This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed. | |
dc.source.uri | https://www.sciencedirect.com/science/article/pii/S096999611930302X | |
dc.subject | Isogenic | en_US |
dc.subject | Induced pluripotent stem cells | en_US |
dc.subject | Neurons | en_US |
dc.subject | SCN1A | en_US |
dc.subject | Genetic epilepsy with febrile seizure plus | en_US |
dc.subject | Electrophysiology | en_US |
dc.subject | Disease modeling | en_US |
dc.title | Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associated SCN1A mutation | en_US |
dc.type | Article | en_US |
dc.identifier.doi | 10.1016/j.nbd.2019.104627 | |