Effect of IVNS1ABP mutation, knockout on gene expression during iPSCs differentiation to Neural Progenitors

We identified a new disease characterized by severe neurological deficits in addition to progeria symptoms. It is caused by IVNSABP gene mutation. The association between IVNS1ABP and aging has never been reported before. By generating isogenic iPSCs from the patients' fibroblasts and differentiating the iPSCs into neural progenitor cells (NPCs), we found that mutant IVNS1ABP fibroblasts, iPSCs, and NPCs exhibited disrupted cytokinesis, DNA damage, and cellular senescence. Transcription analysis of isogenic iPSCs and iPSCs derived neural progenitors (NPCs) also showed impaired cytokinesis and senescence alteration. Correspondingly, cerebral organoids displayed premature differentiation of NPCs to neurons. Molecular profiling as well as biochemical and cellular analysis revealed altered binding of mutant IVNS1ABP to actin and actin-associated proteins and dysregulated actin dynamics during cytokinesis. Taken together, we propose that IVNS1ABP mutation dysregulates actin polymerization and organization which is at least partly responsible for the cellular senescence phenotypes in this undiagnosed disease. Overall design: To get insight into the gene's affection in CNS (central nerve system), we corrected one patient iPSC line, and generated the mutation corrected isogenic iPSC line and KO iPSC line by CRISPR/Cas9. These iPSCs lines were further differentiated to NPCs. We then performed gene expression profiling analysis using data obtained from RNA-seq of the isogenic cell lines (CON, MT and KO), at two tome points (iPSCs and NPCs)