Transcriptomic analysis identifies dysregulated pathways and therapeutic targets in PMM2-CDG
Entity
UAM. Departamento de Biología MolecularPublisher
ElsevierDate
2024-06-01Citation
10.1016/j.bbadis.2024.167163
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1870.5 (2024): 167163
ISSN
0925-4439 (print); 1879-260X (online)DOI
10.1016/j.bbadis.2024.167163Funded by
PID2019-108096RBC21, PID2022-140047OB-C21, European Union (HORIZON-HLTH-2022-DISEASE06, Project ID: 101080580)Project
Gobierno de España. PID2019-108096RB-C21; Gobierno de España. PID2022-140047OB-C21; info:eu-repo/grantAgreement/EC/HE/101080580/EU//EURASEditor's Version
https://doi.org/10.1016/j.bbadis.2024.167163Subjects
PMM2-CDG; Patient-Derived Fibroblasts; Transcriptomics; Systems Biology; Pharmacological Chaperones; Drug Repurposing; RNA-Seq; Biología y Biomedicina / BiologíaRights
© 2024 The AuthorsAbstract
PMM2-CDG (MIM # 212065), the most common congenital disorder of glycosylation, is caused by the deficiency of phosphomannomutase 2 (PMM2). It is a multisystemic disease of variable severity that particularly affects the nervous system; however, its molecular pathophysiology remains poorly understood. Currently, there is no effective treatment. We performed an RNA-seq based transcriptomic study using patient-derived fibroblasts to gain insight into the mechanisms underlying the clinical symptomatology and to identify druggable targets. Systems biology methods were used to identify cellular pathways potentially affected by PMM2 deficiency, including Senescence, Bone regulation, Cell adhesion and Extracellular Matrix (ECM) and Response to cytokines. Functional validation assays using patients' fibroblasts revealed defects related to cell proliferation, cell cycle, the composition of the ECM and cell migration, and showed a potential role of the inflammatory response in the pathophysiology of the disease. Furthermore, treatment with a previously described pharmacological chaperone reverted the differential expression of some of the dysregulated genes. The results presented from transcriptomic data might serve as a platform for identifying therapeutic targets for PMM2-CDG, as well as for monitoring the effectiveness of therapeutic strategies, including pharmacological candidates and mannose-1-P, drug repurposing
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Google Scholar:Gallego Martínez, Diana
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Serrano, Mercedes
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Córdoba-Caballero, José
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Gámez Abascal, María Alejandra
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Seoane Zonjic, Pedro
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Perkins, James R.
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García Ranea, Juan Antonio
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Pérez González, María Belén
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