دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes.
المؤلفون: Puertas-Neyra K; Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain., Coco-Martin RM; Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain. rosa@ioba.med.uva.es.; Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS-REI), Inflamación E Inmunopatologia de Organos y Sistemas, Instituto de Salud Carlos III, Valladolid, Spain. rosa@ioba.med.uva.es.; Centro en Red de Medicina Regenerativa, y Terapia Celular de Castilla y León, Valladolid, Spain. rosa@ioba.med.uva.es., Hernandez-Rodriguez LA; Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain., Gobelli D; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain.; Departamento de Biología Celular, Genética, Histología y Farmacología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain., Garcia-Ferrer Y; Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain., Palma-Vecino R; Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain., Tellería JJ; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain., Simarro M; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain.; Departamento de Biología Celular, Genética, Histología y Farmacología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain., de la Fuente MA; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain.; Departamento de Biología Celular, Genética, Histología y Farmacología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain., Fernandez-Bueno I; Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain.; Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS-REI), Inflamación E Inmunopatologia de Organos y Sistemas, Instituto de Salud Carlos III, Valladolid, Spain.; Centro en Red de Medicina Regenerativa, y Terapia Celular de Castilla y León, Valladolid, Spain.
المصدر: Stem cell research & therapy [Stem Cell Res Ther] 2024 Jul 02; Vol. 15 (1), pp. 192. Date of Electronic Publication: 2024 Jul 02.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101527581 Publication Model: Electronic Cited Medium: Internet ISSN: 1757-6512 (Electronic) Linking ISSN: 17576512 NLM ISO Abbreviation: Stem Cell Res Ther Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : BioMed Central
مواضيع طبية MeSH: Induced Pluripotent Stem Cells*/metabolism , AC133 Antigen*/genetics , AC133 Antigen*/metabolism , Phenotype*, Humans ; Male ; Female ; Targeted Gene Repair/methods ; Retinal Dystrophies/genetics ; Retinal Dystrophies/therapy ; Retinal Dystrophies/pathology ; Adult ; Mutation ; Exome Sequencing ; Exome
مستخلص: 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.
(© 2024. The Author(s).)
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معلومات مُعتمدة: PID2020-118860RB-I00 /AEI/10.13039 /501100011033 Agencia Estatal de Investigación
فهرسة مساهمة: Keywords: CD133; Cone-rod dystrophy; PROM1 gene; Retinal diseases; Retinitis pigmentosa; Stargardt’s type 4 disease; iPSC
المشرفين على المادة: 0 (PROM1 protein, human)
0 (AC133 Antigen)
تواريخ الأحداث: Date Created: 20240703 Date Completed: 20240703 Latest Revision: 20240725
رمز التحديث: 20240726
مُعرف محوري في PubMed: PMC11218195
DOI: 10.1186/s13287-024-03804-2
PMID: 38956727
قاعدة البيانات: MEDLINE
الوصف
تدمد:1757-6512
DOI:10.1186/s13287-024-03804-2