NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL

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 EGF...

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Detalles Bibliográficos
Autores: Bugallo Casal, Ana, Castillo Sánchez, José Antonio, Campos, Francisco
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universidad de Santiago de Compostela (USC)
Repositorio:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
Idioma:inglés
OAI Identifier:oai:dnet:minerva_____::b24b7e1d4759f0394c5dff343b3148f9
Acceso en línea:https://hdl.handle.net/10347/46963
Access Level:acceso abierto
Palabra clave:CADASIL
Disease modeling
Human iPSCs
NOTCH3 variant position
Proteomic analysis
Stem cells
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spelling NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASILBugallo Casal, AnaCastillo Sánchez, José AntonioCampos, FranciscoCADASILDisease modelingHuman iPSCsNOTCH3 variant positionProteomic analysisStem cellsCerebral 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.SpringerUniversidade de Santiago de Compostela. Departamento de Psiquiatría, Radioloxía, Saúde Pública, Enfermaría e Medicina20252025-12-0120252025-12-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10347/46963reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostelainstname:Universidad de Santiago de Compostela (USC)InglésengInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 RD24 0009 ESInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII) PI17%2F00540 IMPLANTACION DE LA MEDICINA PERSONALIZADA PARA EL ESTUDIO Y TRATAMIENTO DE ENFERMEDADES CEREBROVASCULARES COMO CADASIL.Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII) PI20%2F01014 MODELAJE DE PATOLOGIAS VASCULARES EN PACIENTES DE CADASIL CON FENOTIPO LEVE Y SEVERO.Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica, Técnica y de Innovación para el periodo 2021-2023 PI23%2F00890 Caracterización de las alteraciones hemostáticas en pacientes que reciben terapia con células CAR-T y su relación con el desarrollo de complicaciones trombóticas y hemorrágicas.Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica, Técnica y de Innovación para el periodo 2021-2023 AC23_2%2F00029 Historia Natural de CADASILEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 825575open accesshttp://purl.org/coar/access_right/c_abf2© The Author(s) 2025http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:dnet:minerva_____::b24b7e1d4759f0394c5dff343b3148f92026-06-15T12:47:27Z
dc.title.none.fl_str_mv NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL
title NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL
spellingShingle NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL
Bugallo Casal, Ana
CADASIL
Disease modeling
Human iPSCs
NOTCH3 variant position
Proteomic analysis
Stem cells
title_short NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL
title_full NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL
title_fullStr NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL
title_full_unstemmed NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL
title_sort NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL
dc.creator.none.fl_str_mv Bugallo Casal, Ana
Castillo Sánchez, José Antonio
Campos, Francisco
author Bugallo Casal, Ana
author_facet Bugallo Casal, Ana
Castillo Sánchez, José Antonio
Campos, Francisco
author_role author
author2 Castillo Sánchez, José Antonio
Campos, Francisco
author2_role author
author
dc.contributor.none.fl_str_mv Universidade de Santiago de Compostela. Departamento de Psiquiatría, Radioloxía, Saúde Pública, Enfermaría e Medicina
dc.subject.none.fl_str_mv CADASIL
Disease modeling
Human iPSCs
NOTCH3 variant position
Proteomic analysis
Stem cells
topic CADASIL
Disease modeling
Human iPSCs
NOTCH3 variant position
Proteomic analysis
Stem cells
description 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.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025-12-01
2025
2025-12-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10347/46963
url https://hdl.handle.net/10347/46963
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 RD24 0009 ES
Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII) PI17%2F00540 IMPLANTACION DE LA MEDICINA PERSONALIZADA PARA EL ESTUDIO Y TRATAMIENTO DE ENFERMEDADES CEREBROVASCULARES COMO CADASIL.
Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII) PI20%2F01014 MODELAJE DE PATOLOGIAS VASCULARES EN PACIENTES DE CADASIL CON FENOTIPO LEVE Y SEVERO.
Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica, Técnica y de Innovación para el periodo 2021-2023 PI23%2F00890 Caracterización de las alteraciones hemostáticas en pacientes que reciben terapia con células CAR-T y su relación con el desarrollo de complicaciones trombóticas y hemorrágicas.
Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica, Técnica y de Innovación para el periodo 2021-2023 AC23_2%2F00029 Historia Natural de CADASIL
European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 825575
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
© The Author(s) 2025
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
© The Author(s) 2025
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
instname:Universidad de Santiago de Compostela (USC)
instname_str Universidad de Santiago de Compostela (USC)
reponame_str Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
collection Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
repository.name.fl_str_mv
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