Transcriptomic analysis identifies dysregulated pathways and therapeutic targets in PMM2-CDG
Por:
Gallego D, Serrano M, Cordoba-Caballero J, Gámez A, Seoane P, Perkins JR, Ranea JAG and Pérez B
Publicada:
1 jun 2024
Ahead of Print:
1 abr 2024
Resumen:
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.
Filiaciones:
Gallego D:
Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, U746- CIBER de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, 28049 Madrid, Spain
Serrano M:
Pediatric Neurology Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain
U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Spain
Cordoba-Caballero J:
Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Spain
U-741, CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
Gámez A:
Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, U746- CIBER de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, 28049 Madrid, Spain
Seoane P:
Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Spain
U-741, CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
Perkins JR:
Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Spain
U-741, CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
The Biomedical Research Institute of Málaga (IBIMA), Málaga, Spain
Spanish National Bioinformatics Institute (INB/ELIXIR-ES), Madrid, Spain
Ranea JAG:
Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Spain
U-741, CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
The Biomedical Research Institute of Málaga (IBIMA), Málaga, Spain
Spanish National Bioinformatics Institute (INB/ELIXIR-ES), Madrid, Spain
Pérez B:
Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, U746- CIBER de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, 28049 Madrid, Spain
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