B3GALT6 mutations lead to compromised connective tissue biomechanics in Ehlers-Danlos syndrome
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
- Sophie Front
- Anne Robert (ORCID: https://orcid.org/0000-0002-9092-6776)
- Delfien Syx (ORCID: https://orcid.org/0000-0001-9421-4496)
- Sandrine Gulberti (ORCID: https://orcid.org/0000-0002-9378-4697)
- Benjamin Jolivet
- Fransiska Malfait (ORCID: https://orcid.org/0000-0002-5010-0304)
- Alison Wurtz (ORCID: https://orcid.org/0000-0002-9436-3325)
- Sylvie Fournel‐Gigleux (ORCID: https://orcid.org/0000-0001-7782-9448)
- Rebekka Wild (ORCID: https://orcid.org/0000-0003-2025-7228)
- Chrystel Lopin‐Bon (ORCID: https://orcid.org/0000-0002-5146-2905)
- Yasaman Karami (ORCID: https://orcid.org/0000-0001-8413-2665)
- Grégory Francius (ORCID: https://orcid.org/0000-0001-8533-9449)
- Nick Ramalanjaona
- Rachel Onifarasoaniaina (ORCID: https://orcid.org/0000-0002-0355-1882)
- Roméo Diana (ORCID: https://orcid.org/0009-0007-3899-6180)
- Guillermo Barreto (ORCID: https://orcid.org/0000-0002-7777-4712)
- Jean‐Baptiste Vincourt (ORCID: https://orcid.org/0000-0001-7262-4312)
- Sébastien Hergalant (ORCID: https://orcid.org/0000-0001-8456-7992)
- Hamed Khakzad (ORCID: https://orcid.org/0000-0002-8556-0650)
- Marie Bourgeais (ORCID: https://orcid.org/0009-0002-8572-2362)
- Catherine Bui
- Déborah Helle (ORCID: https://orcid.org/0000-0003-0627-5593)
Institutions
- Université d'Orléans (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Ghent University Hospital (BE)
- CEA Grenoble (FR)
- Laboratoire Lorrain de Recherche en Informatique et ses Applications (FR)
- Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (FR)
- Institut de Chimie Organique et Analytique (FR)
- Institut Cochin (FR)
- Institut de Biologie Structurale (FR)
- Ingénierie Moléculaire et Physiopathologie Articulaire (FR)
- Nutrition-Génétique et Exposition aux Risques Environnementaux (FR)
- Université Grenoble Alpes (FR)
- Université de Lorraine (FR)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-08-22
- DOI
- https://doi.org/10.1172/jci.insight.179474
- Citations
- 1
- Primary Topic
- Connective tissue disorders research
- Type
- article
- Field-Weighted Citation Impact
- 1.82
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