Biallelic B3GALT6 mutations cause spondylodysplastic Ehlers–Danlos syndrome

Abstract

Proteoglycans are among the most abundant and structurally complex biomacromolecules and play critical roles in connective tissues. They are composed of a core protein onto which glycosaminoglycan (GAG) side chains are attached via a linker region. Biallelic mutations in B3GALT6, encoding one of the linker region glycosyltransferases, are known to cause either spondyloepimetaphyseal dysplasia (SEMD) or a severe pleiotropic form of Ehlers-Danlos syndromes (EDS). This study provides clinical, molecular and biochemical data on 12 patients with biallelic B3GALT6 mutations. Notably, all patients have features of both EDS and SEMD. In addition, some patients have severe and potential life-threatening complications such as aortic dilatation and aneurysm, cervical spine instability and respiratory insufficiency. Whole-exome sequencing, next generation panel sequencing and direct sequencing identified biallelic B3GALT6 mutations in all patients. We show that these mutations reduce the amount of β3GalT6 protein and lead to a complete loss of galactosyltransferase activity. In turn, this leads to deficient GAG synthesis, and ultrastructural abnormalities in collagen fibril organization. In conclusion, this study redefines the phenotype associated with B3GALT6 mutations on the basis of clinical, molecular and biochemical data in 12 patients, and provides an in-depth assessment of β3GalT6 activity and GAG synthesis to better understand this rare condition.

Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

“…B3GALT6 catalyzes the transfer of the second Gal residue to the growing tetrasaccharide linker region. Mutations in this enzyme cause Spondyloepimetaphyseal dysplasia with joint laxity, Beighton type (SEMDJL1, MIM 271640), known as EDS spondylodysplastic type 2 (EDSSPD2) in the EDS classification, and also called EDS progeroid type 2 (MIM 615349) . Fibroblasts from affected individuals exhibited a large decrease in ability to prime GAG synthesis together with impaired glycation of decorin confirming B3GALT6 loss of function.…”

Classification, nosology and diagnostics of Ehlers-Danlos syndrome

“…Van Damme et al described recently 12 patients with bi-allelic B3GALT6 mutations. 34 The musculocontractural EDS is due to bi-allelic mutations in either CHST14 gene (type 1) or more rarely DSE gene (type 2) and has also considerable clinical overlap with the kyphoscoliotic type. 13,35 Uehara et al described spinal involvement in 12 patients with CHST14 related mcEDS.…”

“…Often this is not possible and therefore there is still room for new types. This is, among other things, due to: -the clinical overlap between many of these EDS types Journal of Biomedicine and Translational Research, 5 (2) 2019, [34][35][36][37][38][39][40][41][42][43][44][45][46] -absence of a pathogenic variant in any of the known EDS associated genes in an important proportion of EDS patients. -the presence of associated features which do not fit into one of the existing types.…”

b3galt6knock-out zebrafish recapitulate β3GalT6-deficiency disorders in human and reveal a trisaccharide proteoglycan linkage region

“…Pathogenic variants in B3GALT6 either result in mislocalization and/or reduced amounts of active galactosyltransferase II [19]. Previous studies on several biallelic B3GALT6 variants showed that they resulted in a barely detectable in vitro galactosyltransferase II enzymatic activity, but intriguingly HS and CS/DS GAG synthesis was partially preserved in cellulo [20]. While some variants may have a greater deleterious effect on the in vitro than on the in cellulo enzymatic activity, it is currently unknown whether there are rescue mechanisms at play to (partially) compensate for the galactosyltransferase II activity.…”

“…GAG: glycosaminoglycan. The columns 'spEDS-B3GALT6' and 'SEMD-JL1' summarize the most important clinical features of all hitherto reported patients for whom this data was available[20,47].…”