Collagens in the Physiopathology of the Ehlers–Danlos Syndromes

Abstract

The Ehlers-Danlos Syndromes (EDS) comprise a clinically and genetically heterogeneous group of complex hereditary disorders of connective tissue, with common features including joint hypermobility, soft and hyperextensible skin, abnormal wound healing, easy bruising, and signs of generalized connective tissue friability. Initial ultrastructural studies suggested that the abnormalities underlying EDS affected the collagen "wickerwork" of the connective tissue, and early biochemical and genetic studies identified defects in fibrillar types I, III, and V collagen, and in enzymes involved in their posttranslational modification, lysyl hydroxylase 1 and the procollagen amino-proteinase ADAMTS2. More recent discoveries have implicated a range of other, diverse extracellular matrix (ECM) molecules in the physiopathology of EDS, including the glycoprotein tenascin X, the FACIT type XII collagen, the intracellular chaperone and peptidylprolyl isomerase FKBP22, enzymes involved in glycosaminoglycan biosynthesis (D4ST1, DS-epi1, galactosyltransferase I and II), an intracellular zinc transporter ZIP13, (putative) transcription factors ZNF469 and PRDM5, factors involved in the classical complement pathway (C1r and C1s), and most recently, the ECM molecule AEBP1 that is involved in collagen polymerization. In this chapter, we give an overview of the different types of EDS and describe how the identification of their molecular underpinnings, and the study of pathophysiologic consequences of these defects in humans and in cellular and mouse models have provided key insights into the complex pathways of collagen fibrillogenesis and supramolecular organization of the collagen fibrils in the ECM.

Analysis of matrisome expression patterns in murine and human dorsal root ganglia

“…Chronic pain is a common worldwide problem with inadequate treatment options (Cohen et al, 2021;Yong et al, 2022). Intriguingly, many pathological conditions associated with extracellular matrix (ECM) alterations are associated with the presence of chronic pain (Berk et al, 2012;Marini et al, 2017;Iozzo and Gubbiotti, 2018;Malfait et al, 2020Malfait et al, , 2021b. Indeed, pain is often the primary reason patients seek medical attention for complex diseases such as osteoarthritis, and for heritable connective tissue disorders like Ehlers-Danlos Syndromes, Marfan Syndrome, and osteogenesis imperfecta (Dean, 2007;Neogi, 2013;Nghiem et al, 2018;Perrot et al, 2019;Malfait et al, 2021a).…”

Local Net Charge State of Collagen Triple Helix Is a Determinant of FKBP22 Binding to Collagen III

“…This complex biosynthetic machinery is collectively termed a molecular ensemble [6][7][8]. Mutations in genes encoding collagen cause many connective tissue disorders such as Osteogenesis Imperfecta (OI) and Ehlers-Danlos Syndrome (EDS), and their pathogenicity can be attributed to reduced levels of collagen proteins or the secretion of mutant collagen proteins [9][10][11][12][13]. Moreover, mutations in members of this molecular ensemble can also cause collagen-related connective tissue disorders, which have already been shown to be a cause of OI, establishing the paradigm of a genetic pathway extending from inside the cell to the extracellular matrix [14][15][16][17][18][19].…”