PLX057903

GSE145656: Investigation of de novo mutations in a schizophrenia case-parent trio by induced pluripotent stem cell based in vitro disease-modelling: Convergence of schizophrenia and autism-related cellular phenotypes

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Background: De novo mutations (DNMs) have been implicated in the etiology of schizophrenia, a chronic debilitating psychiatric disorder characterized by hallucinations, delusions, cognitive dysfunction and poor community functioning. Several DNMs have been shown by examining schizophrenia 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 somatic cell reprogramming to generate induced pluripotent stem cell (iPSC) lines from each member of a schizophrenia 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 schizophrenia 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. After characterization the iPSCs were differentiated into neuronal progenitor cells (NPCs) and hippocampal dentate gyrus granule cells for the investigation of various cellular phenotypes. We used RNASeq to investigate and transcriptomic differences, calcium (Ca2+) imaging, cell proliferation, migration, oxidative stress, and mitochondrial assays to characterize the investigated NPC lines. Results: NPCs derived from the schizophrenia patient exhibited transcriptomic differences related to Wnt-signaling, axonal guidance and synapse formation, and decreased Ca2+ reactivity to glutamate. Moreover we could observe increased cellular proliferation and migration, accelerated neurite outgrowth rates, and alterations in mitochondrial quantity and morphology. Conclusions: The approach of reprograming case-parent trios represents a possibility of investigating disease-causing mutations and comparing cell lines with reduced variation in genetic background. Our results are indicative of an overlap between schizophrenia and autism-related phenotypes in the investigated family. SOURCE: János,Miklós,Réthelyi (rethelyi.janos@med.semmelweis-univ.hu) - Semmelweis University