B3GALT6 mutations lead to compromised connective tissue biomechanics in Ehlers-Danlos syndrome
Year: 2025
Type: article
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.
Source: JCI Insight
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
Institutions: Centre National de la Recherche Scientifique, Ingénierie Moléculaire, Cellulaire et Physiopathologie, Université de Lorraine, Inserm, Nutrition-Génétique et Exposition aux Risques Environnementaux, Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement, Institut national de recherche en sciences et technologies du numérique, Laboratoire Lorrain de Recherche en Informatique et ses Applications, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, CEA Grenoble, Institut de Biologie Structurale, Université Grenoble Alpes, Université Paris Cité, Institut Cochin, Université d'Orléans, Institut de Chimie Organique et Analytique, Ghent University Hospital, Ghent University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Université de Lorraine, Ehlers-Danlos Society, Fondation Maladies Rares, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université d'Orléans, French Infrastructure for Integrated Structural Biology, Vlaamse regering, Fondation Schlumberger pour l’Education et la Recherche, European Regional Development Fund
Awards: G1064512522, Multimolecular Glycosyltransferases complexes involved in glycosaminoglycan-Linker assembly, CBH-EUR-GS, G188123869, G2424985281, G256544642, G2659019386, G2900821844, G374707465, G3932521858, G4055186154, G4062477733, G4199165798, G4399195447, G4733349049, G6255033851, Radiopharmaceutiques Innovants en Oncologie et Neurologie, G6582749931, G678225801, G6803667113, G7116321974, G7240651115, G7311628704, G767938461, Synthèse Organique : des molécules au vivant, G8548513469, Infrastructure Française pour la Biologie Structurale Intégrée
OpenAlex ID: W4413680744