Deciphering disease signatures and molecular targets in vascular Ehlers-Danlos syndrome through transcriptome and miRNome sequencing of dermal fibroblasts

Abstract

Vascular Ehlers-Danlos syndrome (vEDS) is a severe connective tissue disorder caused by dominant mutations in the COL3A1 gene encoding type III collagen (COLLIII). COLLIII is primarily found in blood vessels and hollow organs, and its deficiency leads to soft connective tissues fragility, resulting in life-threatening arterial and organ ruptures. There are no current targeted therapies available. Although the disease usually results from COLLIII misfolding due to triple helix structure disruption, the underlying pathomechanisms are largely unknown. To address this knowledge gap, we performed a comprehensive transcriptome analysis using RNA- and miRNA-seq on a large cohort of dermal fibroblasts from vEDS patients and healthy donors. Our investigation revealed an intricate interplay between proteostasis abnormalities, inefficient endoplasmic reticulum stress response, and compromised autophagy, which may significantly impact the molecular pathology. We also present the first detailed miRNAs expression profile in patient cells, demonstrating that several aberrantly expressed miRNAs can disrupt critical cellular functions involved in vEDS pathophysiology, such as autophagy, proteostasis, and mTOR signaling. Target prediction and regulatory networks analyses suggested potential interactions among miRNAs, lncRNAs, and candidate target genes linked to extracellular matrix organization and autophagy-lysosome pathway. Our results highlight the importance of understanding the functional role of ncRNAs in vEDS pathogenesis, shedding light on possible miRNAs and lncRNAs signatures and their functional implications for dysregulated pathways related to disease. Deciphering this complex molecular network of RNA interactions may yield additional evidence for potential disease biomolecules and targets, assisting in the design of effective patient treatment strategies.