Generation of Induced Pluripotent Stem Cells and Neuroepithelial Stem Cells from a Family with the Pathogenic Variant p.Q337X in Progranulin

Pathogenic <i>GRN</i> variants that reduce progranulin (PGRN) levels cause frontotemporal dementia (FTD). To facilitate model development, we generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts of two family members carrying the <i>GRN</i> c.1009C>T (p.Q337X) pathogenic variant-one symptomatic and one asymptomatic-as well as a non-carrier first-degree relative serving as a genetically matched control. The obtained iPSC lines were validated for pluripotency markers (Nanog, Sox2, Oct4, and TRA1-1-81), genomic integrity, and differentiation potential. The obtained iPSC lines were subsequently directed toward neuroepithelial stem (NES) cells. NES identity was confirmed by the expression of lineage-specific markers, including Nestin and Sox2 (assessed by immunocytochemistry), as well as <i>SOX1</i>, <i>PLAGL1</i>, and <i>MKI67</i> (evaluated by real-time PCR). Furthermore, <i>GRN</i> mRNA levels were significantly reduced in iPSC and NES lines derived from mutation carriers compared to control cells. The established iPSC and NES cell lines represent a platform for modeling progranulin-deficient FTD. The symptomatic and asymptomatic carrier-derived lines obtained from the same family offer a unique opportunity to study disease progression across clinical phases. The control line, derived from a related (first-degree) non-carrier, minimizes genetic background variability. Their utility of the established cell lines extends to therapeutic drug screening and further differentiation into neuronal, non-neuronal, and organoid models.