PhD Scientific Days 2024

Budapest, 9-10 July 2024

Mental Health Sciences II.

Biological consequences of a de novo ZMYND11 mutation in a schizophrenic patient – a human induced pluripotent stem cell-based study

Author(s)

Csongor Tordai1, Katalin Vincze2, Ádám Póti3, Edit Hathy2, Dávid Szűts1, János Réthelyi1, Ágota Apáti3
1: Molecular Psychiatry Research Group, Hungarian Academy of Sciences and Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
2: Molecular Psychiatry Research Group, Hungarian Academy of Sciences and Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary; Molecular Cell Biology Research Group, Institute of Molecular Life Sciences, HUN-REN-Research Centre for Natural Sciences, Budapest, Hungary
3: Molecular Cell Biology Research Group, Institute of Molecular Life Sciences, HUN-REN-Research Centre for Natural Sciences, Budapest, Hungary

Text of the abstract

Introduction: Our research group is focused on models of neurodevelopmental psychiatric disorders using induced pluripotent stem cells (iPSCs) in vitro. We are investigating the biological pathomechanism of schizophrenia, which is characterized by altered brain development and synaptic function. In a previous study, we reprogrammed somatic cells from a schizophrenic patient with a potentially pathogenic de novo mutation in the ZMYND11 gene to iPSCs. As our current knowledge suggests that the hippocampus may play a role in schizophrenia pathogenesis, we differentiated the iPSCs into PROX-1 positive hippocampal dentate gyrus granule neurons.
Aims: The objective of our investigation is to assess the impact of the discovered ZMYND11 mutation on neuronal differentiation, thereby elucidating alterations in gene expression profiles and cell function between the patient-derived cell line and its isogenic controls.
Methods: We used CRISPR-based genome editing to correct the de novo mutation in the patient cell line and introduced the same mutation into a genetically unrelated healthy control cell line. We then differentiated the cells into PROX-1 positive dentate gyrus granule cells using an in vitro protocol. We collected RNA from the patient cell line and isogenic controls at two different time points during the differentiation process (neural progenitor cells and mature hippocampal neurons). We compared the gene expression of the mutant cell lines to wild type ones in both genetic backgrounds. We used calcium imaging to assess the neurons’ reaction to glutamate.
Results: At the neural progenitor level, we observed overexpression of genes involved in neural differentiation and underexpression of genes connected to glial function in the mutant lines. At the neural level, we found overexpression of genes involved in neural function. Further analysis revealed differentially expressed genes involved in synaptic transmission, particularly in the glutamatergic synapse. During calcium imaging experiments we found decreased reaction to glutamate in the patient derived cells.
Conclusion: Our study provides evidence that the de novo mutation of the ZMYND11 gene in this specific schizophrenic patient plays a role in nervous system development and synaptic function and may have contributed to the pathogenesis of schizophrenia.
Funding: NAP 2017-1.2.1-NKP-2017-00002 grant, SE 250+ PhD grant