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Collagens in the Physiopathology of the Ehlers–Danlos Syndromes

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The Collagen Superfamily and Collagenopathies

Part of the book series: Biology of Extracellular Matrix ((BEM,volume 8))

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.

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Abbreviations

AEBP1:

Adipocyte enhancer-binding protein 1

ATCS:

Adducted thumb–clubfoot syndrome

aEDS:

Arthrochalasia type

BCS:

Brittle cornea syndrome

C4ST:

Chondroitin 4-O-sulfotransferase

C:

Carboxy

CAH:

Congenital adrenal hypoplasia

cEDS:

Classical EDS

clEDS:

Classical-like EDS

CS:

Chondroitin sulfate

cvEDS:

Cardiac-valvular EDS

D4ST1:

Dermatan 4-O-sulfotransferase-1

dEDS:

Dermatosparaxis type

DS:

Dermatan sulfate

DS-epi:

Dermatan sulfate epimerase

EDS:

Ehlers–Danlos syndromes

ECM:

Extracellular matrix

ER:

Endoplasmic reticulum

FACIT:

Fibril-associated collagens with interrupted triple helices

GAG:

Glycosaminoglycan

GalNAc:

N-acetylgalactosamine

GalT:

Galactosyltransferase

GlcA:

Glucuronic acid

hEDS:

Hypermobile Ehlers–Danlos syndrome

HPs:

Hydroxylysylpyridinolines

HS:

Heparan sulfate

IdoA:

Iduronic acid

kEDS:

Kyphoscoliotic EDS

LH:

Lysyl hydroxylase

LPs:

Lysylpyridinolines

mcEDS:

Musculocontractural EDS

mEDS:

Myopathic EDS

N:

Amino

NMD:

Nonsense-mediated mRNA decay

OI:

Osteogenesis imperfecta

pEDS:

Periodontal EDS

PPIase:

Peptidylprolyl isomerase

rER:

Rough endoplasmic reticulum

RNAi:

RNA interference

SEMD:

Spondyloepimetaphyseal dysplasia

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SLRP:

Small leucine-rich proteoglycan

spEDS:

Spondylodysplastic EDS

TNX:

Tenascin X

TSP1:

Thrombospondin type I repeats

TSPN:

Thrombospondin N-terminal domain

vEDS:

Vascular EDS

XylTs:

Xylosyltransferases

ZIP13:

Zrt/irt-like protein 13

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Acknowledgments

This work was supported by the Research Foundation Flanders (FWO), Belgium (11B7921N to MC, 12Q5920N to DS, 1842318N to FM and 3G041519 to FM) and a Methusalem Grant from Ghent University (grant number BOFMET2015000401). The authors declare no conflicts of interest.

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  1. Department of Biomolecular Medicine, Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium

    Fransiska Malfait, Robin Vroman, Marlies Colman & Delfien Syx

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Correspondence to Fransiska Malfait .

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    Florence Ruggiero

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Malfait, F., Vroman, R., Colman, M., Syx, D. (2021). Collagens in the Physiopathology of the Ehlers–Danlos Syndromes. In: Ruggiero, F. (eds) The Collagen Superfamily and Collagenopathies. Biology of Extracellular Matrix, vol 8. Springer, Cham. https://doi.org/10.1007/978-3-030-67592-9_3

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