Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes

[Background]: Inherited retinal dystrophies (IRD) are one of the main causes of incurable blindness worldwide. IRD are caused by mutations in genes that encode essential proteins for the retina, leading to photoreceptor degeneration and loss of visual function. IRD generates an enormous global finan...

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Autores: Puertas-Neyra, Kevin, Coco, Rosa M., Hernández-Rodríguez, Leticia A., Gobelli, Dino, García-Ferrer, Yenisey, Palma-Vecino, Raicel, Tellería, Juan José, Simarro-Grande, María, Fuente, Miguel A. de la, Fernández-Bueno, Iván
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/380130
Acesso em linha:http://hdl.handle.net/10261/380130
Access Level:acceso abierto
Palavra-chave:iPSC
Retinal diseases
PROM1 gene
CD133
Retinitis pigmentosa
Cone-rod dystrophy
Stargardt’s type 4 disease
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oai_identifier_str oai:digital.csic.es:10261/380130
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes
title Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes
spellingShingle Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes
Puertas-Neyra, Kevin
iPSC
Retinal diseases
PROM1 gene
CD133
Retinitis pigmentosa
Cone-rod dystrophy
Stargardt’s type 4 disease
title_short Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes
title_full Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes
title_fullStr Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes
title_full_unstemmed Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes
title_sort Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes
dc.creator.none.fl_str_mv Puertas-Neyra, Kevin
Coco, Rosa M.
Hernández-Rodríguez, Leticia A.
Gobelli, Dino
García-Ferrer, Yenisey
Palma-Vecino, Raicel
Tellería, Juan José
Simarro-Grande, María
Fuente, Miguel A. de la
Fernández-Bueno, Iván
author Puertas-Neyra, Kevin
author_facet Puertas-Neyra, Kevin
Coco, Rosa M.
Hernández-Rodríguez, Leticia A.
Gobelli, Dino
García-Ferrer, Yenisey
Palma-Vecino, Raicel
Tellería, Juan José
Simarro-Grande, María
Fuente, Miguel A. de la
Fernández-Bueno, Iván
author_role author
author2 Coco, Rosa M.
Hernández-Rodríguez, Leticia A.
Gobelli, Dino
García-Ferrer, Yenisey
Palma-Vecino, Raicel
Tellería, Juan José
Simarro-Grande, María
Fuente, Miguel A. de la
Fernández-Bueno, Iván
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
CSIC-UVA - Instituto de Biología y Genética Molecular (IBGM)
Junta de Castilla y León
Centro en Red de Medicina regenerativa y Terapia celular de Castilla y León
Banco Santander
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv iPSC
Retinal diseases
PROM1 gene
CD133
Retinitis pigmentosa
Cone-rod dystrophy
Stargardt’s type 4 disease
topic iPSC
Retinal diseases
PROM1 gene
CD133
Retinitis pigmentosa
Cone-rod dystrophy
Stargardt’s type 4 disease
description [Background]: Inherited retinal dystrophies (IRD) are one of the main causes of incurable blindness worldwide. IRD are caused by mutations in genes that encode essential proteins for the retina, leading to photoreceptor degeneration and loss of visual function. IRD generates an enormous global financial burden due to the lack of understanding of a significant part of its pathophysiology, molecular diagnosis, and the near absence of non-palliative treatment options. Patient-derived induced pluripotent stem cells (iPSC) for IRD seem to be an excellent option for addressing these questions, serving as exceptional tools for in-depth studies of IRD pathophysiology and testing new therapeutic approaches.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/380130
url http://hdl.handle.net/10261/380130
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118860RB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118517RB-I00
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 1 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26157166.v1
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 2 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26157555.v1
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 3 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741630.v1
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 4 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741633.v1
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 5 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741636.v1
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 6 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741639.v1
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 7 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741642.v1
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 8 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741645.v1
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 9 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741648.v1
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 10 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741651.v1
Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 11 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741654.v1
https://doi.org/10.1186/s13287-024-03804-2

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dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
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instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypesPuertas-Neyra, KevinCoco, Rosa M.Hernández-Rodríguez, Leticia A.Gobelli, DinoGarcía-Ferrer, YeniseyPalma-Vecino, RaicelTellería, Juan JoséSimarro-Grande, MaríaFuente, Miguel A. de laFernández-Bueno, IvániPSCRetinal diseasesPROM1 geneCD133Retinitis pigmentosaCone-rod dystrophyStargardt’s type 4 disease[Background]: Inherited retinal dystrophies (IRD) are one of the main causes of incurable blindness worldwide. IRD are caused by mutations in genes that encode essential proteins for the retina, leading to photoreceptor degeneration and loss of visual function. IRD generates an enormous global financial burden due to the lack of understanding of a significant part of its pathophysiology, molecular diagnosis, and the near absence of non-palliative treatment options. Patient-derived induced pluripotent stem cells (iPSC) for IRD seem to be an excellent option for addressing these questions, serving as exceptional tools for in-depth studies of IRD pathophysiology and testing new therapeutic approaches.[Methods]: From a cohort of 8 patients with PROM1-related IRD, we identified 3 patients carrying the same variant (c.1354dupT) but expressing three different IRD phenotypes: Cone and rod dystrophy (CORD), Retinitis pigmentosa (RP), and Stargardt disease type 4 (STGD4). These three target patients, along with one healthy relative from each, underwent comprehensive ophthalmic examinations and their genetic panel study was expanded through clinical exome sequencing (CES). Subsequently, non-integrative patient-derived iPSC were generated and fully characterized. Correction of the c.1354dupT mutation was performed using CRISPR/Cas9, and the genetic restoration of the PROM1 gene was confirmed through flow cytometry and western blotting in the patient-derived iPSC lines.[Results]: CES revealed that 2 target patients with the c.1354dupT mutation presented monoallelic variants in genes associated with the complement system or photoreceptor differentiation and peroxisome biogenesis disorders, respectively. The pluripotency and functionality of the patient-derived iPSC lines were confirmed, and the correction of the target mutation fully restored the capability of encoding Prominin-1 (CD133) in the genetically repaired patient-derived iPSC lines.[Conclusions]: The c.1354dupT mutation in the PROM1 gene is associated to three distinct AR phenotypes of IRD. This pleotropic effect might be related to the influence of monoallelic variants in other genes associated with retinal dystrophies. However, further evidence needs to be provided. Future experiments should include gene-edited patient-derived iPSC due to its potential as disease modelling tools to elucidate this matter in question.The study was funded by grant PID2020-118860RB-100 and PID2020-118517RB-I00 funded by MCIN/AEI/https://doi.org/10.13039/501100011033. Programa Estratégico Instituto de Biología y Genética Molecular (IBGM), Junta de Castilla y León (CCVC8485). Consejería de Educación, Junta de Castilla y León (VA172P20). Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León. Kevin Puertas-Neyra was funded by predoctoral contracts UVa2020 (co-funded by Santander Bank) and Junta de Castilla y Leon 2021.Peer reviewedBioMed CentralMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)CSIC-UVA - Instituto de Biología y Genética Molecular (IBGM)Junta de Castilla y LeónCentro en Red de Medicina regenerativa y Terapia celular de Castilla y LeónBanco SantanderConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/380130reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118860RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118517RB-I00Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 1 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26157166.v1Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 2 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26157555.v1Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 3 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741630.v1Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 4 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741633.v1Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 5 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741636.v1Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 6 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741639.v1Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 7 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741642.v1Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 8 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741645.v1Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 9 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741648.v1Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 10 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741651.v1Puertas-Neyra, Kevin; Coco, Rosa M.; Hernández-Rodríguez, Leticia A.; Gobelli, Dino; García-Ferrer, Yenisey; Palma-Vecino, Raicel; Tellería, Juan José; Simarro-Grande, María; Fuente, Miguel A. de la; Fernández-Bueno, Iván; 2024; Additional file 11 of Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26741654.v1https://doi.org/10.1186/s13287-024-03804-2Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3801302026-05-22T06:33:51Z
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