POGZ heterozygous mutations in neural progenitor cells

Intellectual disability (ID) and autism spectrum disorders (ASD) are complexneurodevelopmental conditions with high genetic heterogeneity. Studies indicate that10%-40% of individuals with ID also have ASD, suggesting shared molecular mechanismsbetween these disorders. Recent next-generation sequencing studies havehighlighted a significant role of de novo mutations in ASD, particularly those with largeeffects. Among these, POGZ (Pogo Transposable Element with zinc fingerdomain) has emerged as a frequently mutated gene with potential loss-of-function effectsin ASD patients. This study investigated the cellular and molecular mechanisms by which POGZmutations contribute to neurodevelopmental disorders (NDDs) using human inducedpluripotent stem cells (iPSCs) derived from patient and CRISPR/Cas9-mediated geneediting to introduce heterozygous POGZ mutations. These mutant iPSCs weredifferentiated into neural progenitor cells (NPCs) and neurons under both two-dimensional (2D) and three-dimensional (3D) culture conditions to analyze the effects ofPOGZ mutations on neural development. Analysis of thetranscriptome via RNA sequencing revealed widespread changes in gene expression inNPCs carrying POGZ mutations. These alterations were significantly enriched for genesinvolved in mitotic chromatid segregation, DNA repair, nonsense-mediated decay, andalternative splicing. Notably, the data revealed a transcriptomic signature characterizedby the elevated expression of neuron-specific genes, suggesting an "accelerated differentiation phenotype in mutant NPCs, mirroring the behavior observed in the 3Dneurosphere models.