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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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Hauptverfasser: Malfait, Fransiska (VerfasserIn) , Kariminejad, Ariana (VerfasserIn) , Van Damme, Tim (VerfasserIn) , Gauche, Caroline (VerfasserIn) , Syx, Delfien (VerfasserIn) , Merhi-Soussi, Faten (VerfasserIn) , Gulberti, Sandrine (VerfasserIn) , Symoens, Sofie (VerfasserIn) , Vanhauwaert, Suzanne (VerfasserIn) , Willaert, Andy (VerfasserIn) , Bozorgmehr, Bita (VerfasserIn) , Kariminejad, Mohamad Hasan (VerfasserIn) , Ebrahimiadib, Nazanin (VerfasserIn) , Haußer-Siller, Ingrid (VerfasserIn) , Huysseune, Ann (VerfasserIn) , Fournel-Gigleux, Sylvie (VerfasserIn) , De Paepe, Anne (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: May 9, 2013
In: The American journal of human genetics
Year: 2013, Jahrgang: 92, Heft: 6, Pages: 935-945
ISSN:1537-6605
DOI:10.1016/j.ajhg.2013.04.016
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ajhg.2013.04.016
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0002929713001778
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 17.08.2021
Beschreibung:Online Resource
ISSN:1537-6605
DOI:10.1016/j.ajhg.2013.04.016

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