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

• DOI: 10.21203/rs.2.20699/v2
• Publication Date: 2020-08-12T20:33:55Z
• Authors: Edit Hathy; Eszter Szabó; Nóra Varga; Zsuzsa Erdei; Csongor Tordai; Boróka Czehlár; Máté Baradits; Bálint Jezsó; Júlia Koller; László Nagy; Mária Judit Molnár; Zsófia Nemoda; László Homolya; Ágota Apáti; János M Réthelyi
• Keywords: Reprogramming

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 identified examining SZ cases their unaffected parents, however most biological significance these remains elusive. To overcome this limitation, we developed an approach using induced pluripotent stem cell (iPSC) lines from each member case-parent trio, order to investigate effects cellular progenies interest, particularly dentate gyrus neuronal progenitors. Methods: We male patient early disease onset negative symptoms, who is carrier 3 non-synonymous genes LRRC7, KHSRP, KIR2DL1. iPSC were generated his parents’ peripheral blood mononuclear cells Sendai virus-based reprogramming differentiated into progenitor (NPCs) hippocampal granule cells. used RNASeq explore transcriptomic differences, calcium (Ca 2+ ) imaging, proliferation, migration, oxidative stress, mitochondrial assays characterize investigated NPC lines. Results: NPCs derived exhibited differences related Wnt-signaling, differentiation, axonal guidance synaptic function, Ca reactivity glutamate. Moreover, could observe increased alterations quantity morphology. Conclusions: The reprograming trios represents opportunity for investigating molecular disease-causing mutations, comparing with reduced variation genetic background. Our results are indicative partial overlap between autism-related phenotypes family. Limitations: study only one family, therefore generalizability findings limited. not derive iPSCs two other siblings test possible family that driven DNMs. functional limited stage, although variables should also be at mature stage.