Transcriptomic analysis identifies dysregulated pathways and therapeutic targets in PMM2-CDG.
Biochim Biophys Acta Mol Basis Dis
; 1870(5): 167163, 2024 Jun.
Article
in En
| MEDLINE
| ID: mdl-38599261
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phosphotransferases (Phosphomutases)
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Congenital Disorders of Glycosylation
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Fibroblasts
Limits:
Female
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Humans
/
Male
Language:
En
Journal:
Biochim Biophys Acta Mol Basis Dis
Year:
2024
Document type:
Article
Affiliation country:
España