Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder
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 (β3G...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
May 9, 2013
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| In: |
The American journal of human genetics
Year: 2013, Volume: 92, Issue: 6, Pages: 935-945 |
| ISSN: | 1537-6605 |
| DOI: | 10.1016/j.ajhg.2013.04.016 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ajhg.2013.04.016 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0002929713001778 
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| Author Notes: | Fransiska Malfait, Ariana Kariminejad, Tim Van Damme, Caroline Gauche, Delfien Syx, Faten Merhi-Soussi, Sandrine Gulberti, Sofie Symoens, Suzanne Vanhauwaert, Andy Willaert, Bita Bozorgmehr, Mohamad Hasan Kariminejad, Nazanin Ebrahimiadib, Ingrid Hausser, Ann Huysseune, Sylvie Fournel-Gigleux, and Anne De Paepe |
| Summary: | 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 (β3GalT6), 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 β3GalT6 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 β3GalT6 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 β3GalT6 in multiple major developmental and pathophysiological processes. |
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| Item Description: | Gesehen am 17.08.2021 |
| Physical Description: | Online Resource |
| ISSN: | 1537-6605 |
| DOI: | 10.1016/j.ajhg.2013.04.016 |