Transcriptomic analysis identifies dysregulated pathways and therapeutic targets in PMM2-CDG
Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1870 |
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| Enthalten in: |
Biochimica et biophysica acta. Molecular basis of disease - 1870(2024), 5 vom: 08. Apr., Seite 167163 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gallego, Diana [VerfasserIn] |
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| Links: |
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| Themen: |
Drug repurposing |
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| Anmerkungen: |
Date Revised 25.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1016/j.bbadis.2024.167163 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Drug repurposing | |
| 650 | 4 | |a PMM2-CDG | |
| 650 | 4 | |a Patient-derived fibroblasts | |
| 650 | 4 | |a Pharmacological chaperones | |
| 650 | 4 | |a RNA-seq | |
| 650 | 4 | |a Systems biology | |
| 650 | 4 | |a Transcriptomics | |
| 700 | 1 | |a Serrano, Mercedes |e verfasserin |4 aut | |
| 700 | 1 | |a Cordoba-Caballero, Jose |e verfasserin |4 aut | |
| 700 | 1 | |a Gámez, Alejandra |e verfasserin |4 aut | |
| 700 | 1 | |a Seoane, Pedro |e verfasserin |4 aut | |
| 700 | 1 | |a Perkins, James R |e verfasserin |4 aut | |
| 700 | 1 | |a Ranea, Juan A G |e verfasserin |4 aut | |
| 700 | 1 | |a Pérez, Belén |e verfasserin |4 aut | |
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