Collagens in the Physiopathology of the Ehlers–Danlos Syndromes

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.