Defective Initiation of Glycosaminoglycan Synthesis due to B3GALT6 Mutations Causes a Pleiotropic Ehlers-Danlos Syndrome-like Connective Tissue Disorder. F. Malfait1, A. Kariminejad2, T. Van Damme1, C. Gauche3, D. Syx1, F. Merhi-Soussi3, S. Gulberti3, S. Symoens1, S. Vanhauwaert1, A. Willaert1, B. Bozorgmehr2, M. Kariminejad2, I. Hausser4, S. Fournel-Gigleux3, A. De Paepe1 1) Center for Medical Genetics Ghent University Hospital, Gent, Belgium; 2) Kariminejad-Najmabadi Pathology & Genetics Center, 1143 Med. 4th Str. Third Phase, Shahrak Gharb, 14656 Tehran, Iran; 3) UMR 7365 CNRS-Université de Lorraine (Ingénierie Moléculaire et Pharmacologie Articulaire, IMoPA), MolCelTEG Team, Biopôle UL, Faculté de Médecine, 54505 Vandoeuvre-lès-Nancy, France; 4) Department of Dermatology, University of Heidelberg, 69120 Heidelberg, Germany.

   Proteoglycans are important components of cell plasma membranes and extracellular matrices of connective tissues. They consist of glycosaminoglycan chains attached to a core protein via a tetrasaccharide linkage, whereby the addition of the third residue is catalyzed by galactosyltransferase II (3GalT6), encoded by B3GALT6. Homozygosity mapping and candidate gene sequence analysis in three independent families, presenting a severe autosomal-recessive connective tissue disorder characterized by skin fragility, delayed wound healing, joint hyperlaxity and contractures, muscle hypotonia, intellectual disability, and a spondyloepimetaphyseal dysplasia with bone fragility and severe kyphoscoliosis, identified biallelic B3GALT6 mutations, including homozygous missense mutations in family 1 (c.619G>C [p.Asp207His]) and family 3 (c.649G>A [p.Gly217Ser]) and compound heterozygous mutations in family 2 (c.323_344del [p.Ala108Glyfs*163], c.619G>C [p.Asp207His]). The phenotype overlaps with several recessive Ehlers-Danlos variants and spondyloepimetaphyseal dysplasia with joint hyperlaxity. Affected individuals' fibroblasts exhibited a large decrease in ability to prime glycosaminoglycan synthesis together with impaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming 3GalT6 loss of function. Dermal electron microcopy disclosed abnormalities in collagen fibril organization, in line with the important regulatory role of decorin in this process. A strong reduction in heparan sulfate level was also observed, indicating that 3GalT6 deficiency alters synthesis of both main types of glycosaminoglycans. In vitro wound healing assay revealed a significant delay in fibroblasts from two index individuals, pointing to a role for glycosaminoglycan defect in impaired wound repair in vivo. Our study emphasizes a crucial role for 3GalT6 in multiple major developmental and pathophysiological processes.

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