Molecular signatures of HNRNPH2 R114W in brain organoids
HNRNPH2 encodes a predominantly nuclear RNA binding protein that facilitates the maturation of RNA into functional mRNA, primarily through the regulation of pre-mRNA splicing. Accurate RNA processing is essential for early brain development, as it controls the timing and localization of neurodevelopmental gene expression regulated by the hnRNP family of proteins. The present study investigates the HNRNPH2 R114W variant using a controlled model system. A patient-derived induced pluripotent stem cell (iPSC) line harboring the mutation is directly compared to a CRISPR-corrected isogenic line in which the R114W variant is reverted to wild type, minimizing confounding effects from other genetic variations and enabling more direct attribution of observed molecular changes to the mutation itself.To bridge mechanistic understanding and therapeutic development, human brain organoids derived from these iPSCs are employed as an in vitro model. These organoids recapitulate key cellular and molecular aspects of early brain development. This controlled system enables quantification of the effects of the R114W mutation on gene regulation and RNA processing. The therapeutic component evaluates antisense oligonucleotides (ASOs) as targeted RNA-based interventions. A structured assay framework is implemented to determine whether candidate ASOs can modulate molecular signatures associated with the R114W mutation in this model.