NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL
Bugallo-Casal, A. (Instituto de Investigación Sanitaria de Santiago (IDIS))
Muiño, Elena (Institut de Recerca Sant Pau)
Bravo, S.B. (Instituto de Investigación Sanitaria de Santiago (IDIS))
Hervella, P. (Instituto de Investigación Sanitaria de Santiago (IDIS))
Arias-Rivas, S. (Hospital Clínico Universitario)
Rodríguez-Yáñez, M. (Hospital Clínico Universitario)
Vara-León, E. (Fundación Pública Gallega de Medicina Genómica)
Quintas-Rey, R. (Instituto de Investigación Sanitaria de Santiago (IDIS))
Pérez-Gayol, L. (Instituto de Investigación Sanitaria de Santiago (IDIS))
Maisterra-Santos, Olga (Hospital Universitari Vall d'Hebron)
Pizarro Gonzálvez, Jesús (Hospital Universitari Vall d'Hebron)
Martorell-Riera, M.R. (Hospital Universitari Son Espases (Palma de Mallorca, Balears))
Vives-Bauzá, C. (Hospital Universitari Son Espases (Palma de Mallorca, Balears))
Fernandez-Cadenas, Israel (Institut de Recerca Sant Pau)
Castillo, J. (Instituto de Investigación Sanitaria de Santiago (IDIS))
Campos, Francisco (Instituto de Investigación Sanitaria de Santiago (IDIS))
Universitat Autònoma de Barcelona

Date:	2025
Abstract:	Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic form of stroke. It is caused by a cysteine-altering variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of Notch3. NOTCH3 pathogenic variants in EGFr 1-6 are associated with high disease severity, whereas those in EGFr 7-34 are associated with late stroke onset and increased survival. However, whether and how the position of the NOTCH3 variant directly affects the disease severity remains unclear. In this study, we aimed to generate human-induced pluripotent stem cells (hiPSCs) from patients with CADASIL with EGFr 1-6 and 7-34 pathogenic variants to evaluate whether the NOTCH3 position affects the cell phenotype and protein profile of the generated hiPSCs lines. Six hiPSCs lines were generated: two from patients with CADASIL with EGFr 1-6 pathogenic variants, two from patients with EGFr 7-34 variants, and two from controls. Notch3 aggregation and protein profiles were tested in the established six hiPSCs lines. Cell analysis revealed that the NOTCH3 variants did not limit the cell reprogramming efficiency. However, EGFr 1-6 variant position was associated with increased accumulation of Notch3 protein in pluripotent stem cells and proteomic changes related with cytoplasmic reorganization mechanisms. In conclusion, our analysis of hiPSCs derived from patients with CADASIL support the clinical association between the NOTCH3 variant position and severity of CADASIL.
Grants:	Instituto de Salud Carlos III PI17/00540 Instituto de Salud Carlos III PI20/01014
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	NOTCH3 variant position ; CADASIL ; Disease modeling ; Human iPSCs ; Proteomic analysis ; Stem cells
Published in:	Neuromolecular medicine, Vol. 27 Núm. 1 (december 2025) , p. 18, ISSN 1559-1174

DOI: 10.1007/s12017-025-08840-6
PMID: 40016442

15 p, 5.4 MB

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