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Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
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Genes 2019, 10(8), 609; https://doi.org/10.3390/genes10080609
Received: 26 June 2019 / Revised: 30 July 2019 / Accepted: 9 August 2019 / Published: 12 August 2019
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Abstract

The Ehlers‒Danlos syndromes (EDS) constitute a heterogenous group of connective tissue disorders characterized by joint hypermobility, skin abnormalities, and vascular fragility. The latest nosology recognizes 13 types caused by pathogenic variants in genes encoding collagens and other molecules involved in collagen processing and extracellular matrix (ECM) biology. Classical (cEDS), vascular (vEDS), and hypermobile (hEDS) EDS are the most frequent types. cEDS and vEDS are caused respectively by defects in collagen V and collagen III, whereas the molecular basis of hEDS is unknown. For these disorders, the molecular pathology remains poorly studied. Herein, we review, expand, and compare our previous transcriptome and protein studies on dermal fibroblasts from cEDS, vEDS, and hEDS patients, offering insights and perspectives in their molecular mechanisms. These cells, though sharing a pathological ECM remodeling, show differences in the underlying pathomechanisms. In cEDS and vEDS fibroblasts, key processes such as collagen biosynthesis/processing, protein folding quality control, endoplasmic reticulum homeostasis, autophagy, and wound healing are perturbed. In hEDS cells, gene expression changes related to cell-matrix interactions, inflammatory/pain responses, and acquisition of an in vitro pro-inflammatory myofibroblast-like phenotype may contribute to the complex pathogenesis of the disorder. Finally, emerging findings from miRNA profiling of hEDS fibroblasts are discussed to add some novel biological aspects about hEDS etiopathogenesis. View Full-Text
Keywords: autophagy; collagen III; collagen V; Ehlers‒Danlos syndrome; endoplasmic reticulum; extracellular matrix; fibroblast-to-myofibroblast transition; miRNA; transcriptome; wound healing autophagy; collagen III; collagen V; Ehlers‒Danlos syndrome; endoplasmic reticulum; extracellular matrix; fibroblast-to-myofibroblast transition; miRNA; transcriptome; wound healing
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Chiarelli, N.; Ritelli, M.; Zoppi, N.; Colombi, M. Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes. Genes 2019, 10, 609.

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