Transcriptomic analysis identifies dysregulated pathways and therapeutic targets in PMM2-CDG.

Area of Science:

• Biochemistry and Molecular Biology
• Genetics and Genomics
• Cell Biology

Background:

• PMM2-CDG is the most common congenital disorder of glycosylation, caused by phosphomannomutase 2 (PMM2) deficiency.
• It is a multisystemic disorder with variable severity, particularly affecting the nervous system, but its molecular pathophysiology is poorly understood.
• No effective treatments are currently available for PMM2-CDG.

Purpose of the Study:

• To gain insight into the molecular mechanisms underlying PMM2-CDG symptomatology using patient-derived fibroblasts.
• To identify potential druggable targets for PMM2-CDG.
• To explore the role of cellular pathways and inflammatory responses in the disease.

Main Methods:

• RNA-sequencing (RNA-seq) based transcriptomic study on patient-derived fibroblasts.
• Systems biology approaches to identify affected cellular pathways (Senescence, Bone regulation, Cell adhesion, Extracellular Matrix (ECM), Response to cytokines).
• Functional validation assays including cell proliferation, cell cycle, ECM composition, and cell migration assessments.

Main Results:

• Transcriptomic analysis revealed dysregulated pathways including senescence, bone regulation, cell adhesion, ECM, and cytokine response.
• Functional assays confirmed defects in cell proliferation, cell cycle, ECM composition, and cell migration in patient fibroblasts.
• An inflammatory response was implicated in the disease pathophysiology, and a pharmacological chaperone partially reverted gene expression changes.

Conclusions:

• Transcriptomic data provides a platform for identifying therapeutic targets for PMM2-CDG.
• The study highlights potential therapeutic strategies including pharmacological chaperones and mannose-1-P for drug repurposing.
• Understanding molecular pathophysiology is crucial for developing effective treatments and monitoring therapeutic efficacy.