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.

Homozygosity for Frameshift Mutations in XYLT2 Result in a Spondylo-Ocular Syndrome with Bone Fragility, Cataracts, and Hearing Defects

“…This indicates that we would not expect XylT2 deficiency to affect articular cartilage, but growth plate cartilage might require both XylT1 and XylT2 activity. Therefore, defects in XYLT1 or those in the remaining enzymatic steps of linker assembly would be expected to affect growth cartilage, and this is supported by observations made in individuals with hypomorphic mutations in XYLT1 and mutations in B4GALT7 (beta1,4-galacosyltransferase 7), B3GALT6 (beta1,3-galactosyltransferase 6) (MIM: 604327), and B3GAT3 (beta1,3-glucuronyltransferase 3) (glucuronyltransferase I) (MIM: 606374) who have significant short stature 6,24,25 (MIM: 606374, 604327).…”

“…5 Three additional sugar residues of the linker region are then added as galactose-galactoseglucuronic acid. Defects at each step of these sugar additions causes various autosomal-recessive disorders (MIM: 604327, 606374), 6,7 illustrating the importance of PG in tissue homeostasis. XYLT1 and XYLT2 are very similar in function and are co-expressed in many tissues, but some temporal, spatial, and tissue-specific differences in expression exist 5,8 and at the cellular level one or the other can be exclusively expressed.…”

Xylose phosphorylation functions as a molecular switch to regulate proteoglycan biosynthesis

“…Inactivating mutations in human GALT-II were recently shown to cause Ehlers-Danlos-like syndrome, which is characterized by a spectrum of skeletal and connective tissue disorders (16,38). Genetic screens in zebrafish have established that FAM20B is essential for proper development of cartilage and bone (8).…”

Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome

“…22 This deficiency results in a loss of cohesion of the tissue, which has been further demonstrated by the ultrastructural study showing abnormal connective tissue. 23 In the last few years, the impairment of proteoglycan synthesis has been involved in a few human connective tissue disorders, namely, (1) SED with dislocations due to CHST3 mutations responsible for a defect in carbohydrate chondroitin 6-sulfotransferase with defective sulfation of chondroitin proteoglycan, 8,24 (2) Desbuquois dysplasia due to CANT1 mutations responsible for a defect in GAG synthesis, 9,25 (3) a chondrodysplasia with joint dislocations due to mutations in IMPAD1 (inositol monophosphatase domaincontaining protein 1) encoding the Golgi resident nucleotide phosphatase gPAPP, and responsible for a defect in sulfated substrates, 26 (4) 'a Larsen-like' phenotype with cardiac defects due to B3GAT3 (galactosyltransferase) mutations 27 and affecting, through the linker synthesis defect, dermatan heparan and chondrotin sulfate proteoglycans and (5) very recently, a spondyloepimetaphyseal dysplasia with joint laxity type 1 and a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation and spinal deformity due to B3GALT6 mutations 28 (Supplementary Table).…”