Investigation of de novo mutations in a schizophrenia case-parent trio by induced pluripotent stem cell-based in vitro d
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RESEARCH
Open Access
Investigation of de novo mutations in a schizophrenia case-parent trio by induced pluripotent stem cell-based in vitro disease modeling: convergence of schizophreniaand autism-related cellular phenotypes Edit Hathy1, Eszter Szabó2, Nóra Varga2, Zsuzsa Erdei2, Csongor Tordai1, Boróka Czehlár1, Máté Baradits1, Bálint Jezsó2, Júlia Koller3, László Nagy4, Mária Judit Molnár3, László Homolya2, Zsófia Nemoda5, Ágota Apáti2* and János M. Réthelyi1,6*
Abstract Background: De novo mutations (DNMs) have been implicated in the etiology of schizophrenia (SZ), a chronic debilitating psychiatric disorder characterized by hallucinations, delusions, cognitive dysfunction, and decreased community functioning. Several DNMs have been identified by examining SZ cases and their unaffected parents; however, in most cases, the biological significance of these mutations remains elusive. To overcome this limitation, we have developed an approach of using induced pluripotent stem cell (iPSC) lines from each member of a SZ case-parent trio, in order to investigate the effects of DNMs in cellular progenies of interest, particularly in dentate gyrus neuronal progenitors. Methods: We identified a male SZ patient characterized by early disease onset and negative symptoms, who is a carrier of 3 non-synonymous DNMs in genes LRRC7, KHSRP, and KIR2DL1. iPSC lines were generated from his and his parents’ peripheral blood mononuclear cells using Sendai virus-based reprogramming and differentiated into neuronal progenitor cells (NPCs) and hippocampal dentate gyrus granule cells. We used RNASeq to explore transcriptomic differences and calcium (Ca2+) imaging, cell proliferation, migration, oxidative stress, and mitochondrial assays to characterize the investigated NPC lines. (Continued on next page)
* Correspondence: [email protected]; [email protected]; [email protected] 2 Molecular Cell Biology Research Group, Institute of Enzymology, Research Center for Natural Sciences, 1117 Magyar tudósok körútja 2, Budapest, Hungary 6 Department of Psychiatry and Psychotherapy, Semmelweis University, Balassa utca 6, Budapest 1083, Hungary Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, v
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