Postdoc Max Planck Institute for Psycholinguistics Nijmegen, Netherlands
Abstract: Haploinsufficiency of the SETBP1 gene causes a highly heterogeneous neurodevelopmental syndrome (SETBP1-haploinsufficiency disorder) with the main phenotypic features including moderate-to-severe speech and language impairments, and wide variability in intellectual functioning. The precise functions of SETBP1, encoding the SET-binding protein, are yet to be discovered. Therefore, the neurobiological pathways by which rare loss-of function SETBP1 variants cause a neurodevelopmental disorder remain largely unknown. By employing induced pluripotent stem cell (iPSC)-derived neural organoids and transcriptomic approaches, we aim to dissect the underlying aetiological pathways. We have generated iPSCs from three patients carrying heterozygous de novo truncating variants and sex-matched parents as controls, and SETBP1-knockout iPSCs with CRISPR/Cas9 gene-editing. These iPSC lines were differentiated into un-patterned neural organoids and their transcriptomic profiles were analysed at whole organoid and single-cell levels. Morphological examination, cell-type specific differential gene expression analysis and cell lineage tracing were performed at two selected developmental timepoints. Both patient-derived and SETBP1-knockout organoids consistently showed gross morphological differences, rosette and transcriptomic anomalies during early organoid development, suggesting aberrations in cell fate commitment during embryonic brain development. Gene ontology analyses demonstrated that dysregulated pathways were related to brain morphogenesis, cilia organisation, axon projection and synaptic function. Together, our work is, to our knowledge, the first mechanistic investigation using iPSCs and organoids derived from SETBP1-haploinsufficiency disorder patients. This work promises to offer valuable insights into the fundamental understanding of the currently unknown neurodevelopmental roles of SETBP1 and aetiological mechanisms that go awry in SETBP1-haploinsufficiency disorder.
Funding Source: SETBP1 Society Pilot Grant Award 2019, UPenn Orphan Disease Center Million Dollar Bike Ride Grant Award 2023
