title: Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder.
abstract: 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.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium. Electronic address: fransiska.malfait@ugent.be.
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.forename: Tim
authors.initials: T
authors.lastname: Van Damme
authors.forename: Caroline
authors.initials: C
authors.lastname: Gauche
authors.forename: Delfien
authors.initials: D
authors.lastname: Syx
authors.forename: Faten
authors.initials: F
authors.lastname: Merhi-Soussi
authors.forename: Sandrine
authors.initials: S
authors.lastname: Gulberti
authors.forename: Sofie
authors.initials: S
authors.lastname: Symoens
authors.forename: Suzanne
authors.initials: S
authors.lastname: Vanhauwaert
authors.forename: Andy
authors.initials: A
authors.lastname: Willaert
authors.forename: Bita
authors.initials: B
authors.lastname: Bozorgmehr
authors.forename: Mohamad Hasan
authors.initials: MH
authors.lastname: Kariminejad
authors.forename: Nazanin
authors.initials: N
authors.lastname: Ebrahimiadib
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Ann
authors.initials: A
authors.lastname: Huysseune
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel-Gigleux
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D004535:Ehlers-Danlos Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics*; D056726:Genetic Association Studies; D058685:Genetic Pleiotropy; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011859:Radiography; D017422:Sequence Analysis, DNA; D014945:Wound Healing / Q000235:genetics
chemical_list: D006025:Glycosaminoglycans; C425302:B3GALT6 protein, human; D005700:Galactosyltransferases