Abstract
Ehlers-Danlos syndromes (EDS) comprise a genetically and clinically heterogenous group of rare diseases that cause severe, often fatal, damage to connective tissue. The molecular basis of EDS implicates defects in extracellular matrix components, including various fibrillar collagens and glycosaminoglycans (GAGs). However, the precise pathogenic mechanisms behind EDS remain elusive. Here, we have implemented a multi-tiered approach to demonstrate the functional impact of B3GALT6 mutations on biochemical and developmental processes, ultimately leading to the spondylodysplastic subtype of EDS (spEDS), characterized by severe musculoskeletal symptoms. We show that the loss of function of β1,3-galactosyltransferase 6 (β3GalT6) is partially compensated by β1,3-glucuronosyltransferase 3 (GlcAT-I), the next enzyme in the GAG biosynthetic pathway. In addition, results from transcriptomics, collagen analysis, and biophysical experiments revealed that impaired collagen maturation, including defective glycosylation of collagen XII, contributes to altered tissue structure and biomechanics, the hallmarks of spEDS. Our findings unravel a new pathogenic mechanism of spEDS and bring us one step closer to therapeutic strategies, including cell and tissue engineering.
Authors
Roméo Milan Diana, Benjamin Jolivet, Jean-Baptiste Vincourt, Sébastien Hergalant, Grégory Francius, Yasaman Karami, Hamed Khakzad, Rebekka Wild, Marie Bourgeais, Anne Robert, Alison Wurtz, Guillermo Barreto, Nick Ramalanjaona, Déborah Helle, Rachel Onifarasoaniaina, Sophie Front, Chrystel Lopin-Bon, Delfien Syx, Fransiska Malfait, Sylvie Fournel-Gigleux, Sandrine Gulberti, Catherine Bui
Figure 5
Transcriptome analysis of dermal fibroblasts from patients with spEDS reveals dysregulated collagen maturation and developmental pathways.
