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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\n                    <jats:italic>B3GALT6<\/jats:italic>\n                    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 \u03b21,3-galactosyltransferase 6 (\u03b23GalT6) is partially compensated by \u03b21,3-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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.179474","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T18:24:22Z","timestamp":1756232662000},"source":"Crossref","is-referenced-by-count":5,"title":["B3GALT6 mutations lead to compromised connective tissue biomechanics in Ehlers-Danlos syndrome"],"prefix":"10.1172","volume":"10","author":[{"given":"Rom\u00e9o Milan","family":"Diana","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Lorraine, CNRS, IMoPA, UMR 7365, F-54000 Nancy, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Jolivet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, CNRS, IMoPA, UMR 7365, F-54000 Nancy, 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