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

Pathogenic GRN 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 GRN 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 SOX1, PLAGL1, and MKI67 (evaluated by real-time PCR). Furthermore, GRN 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.