The clinical and mutational spectrum of B3GAT3 linkeropathy: two case reports and literature review

Abstract

Background: Proteoglycans are large and structurally complex macromolecules which can be found in abundancy in the extracellular matrix and on the surface of all animal cells. Mutations in the genes encoding the enzymes responsible for the formation of the tetrasaccharide linker region between the proteoglycan core protein and the glycosaminoglycan side chains lead to a spectrum of severe and overlapping autosomal recessive connective tissue disorders, collectively coined the 'glycosaminoglycan linkeropathies'.

Results: We report the clinical findings of two novel patients with a complex linkeropathy due to biallelic mutations in B3GAT3, the gene that encodes glucuronosyltransferase I, which catalyzes the addition of the ultimate saccharide to the linker region. We identified a previously reported c.667G > A missense mutation and an unreported homozygous c.416C > T missense mutation. We also performed a genotype and phenotype-oriented literature overview of all hitherto reported patients harbouring B3GAT3 mutations. A total of 23 patients from 10 families harbouring bi-allelic mutations and one patient with a heterozygeous splice-site mutation in B3GAT3 have been reported. They all display a complex phenotype characterized by consistent presence of skeletal dysplasia (including short stature, kyphosis, scoliosis and deformity of the long bones), facial dysmorphology, and spatulate distal phalanges. More variably present are cardiac defects, joint hypermobility, joint dislocations/contractures and fractures. Seven different B3GAT3 mutations have been reported, and although the number of patients is still limited, some phenotype-genotype correlations start to emerge. The more severe phenotypes seem to have mutations located in the substrate acceptor subdomain of the catalytic domain of the glucuronosyltransferase I protein while more mildly affected phenotypes seem to have mutations in the NTP-sugar donor substrate binding subdomain.

Conclusions: Loss-of-function mutations in B3GAT3 are associated with a complex connective tissue phenotype characterized by disproportionate short stature, skeletal dysplasia, facial dysmorphism, spatulate distal phalanges and -to a lesser extent- joint contractures, joint hypermobility with dislocations, cardiac defects and bone fragility. Based on the limited number of reported patients, some genotype-phenotype correlations start to emerge.

Keywords: B3GAT3; Connective tissue; GAG Linkeropathies; Genotype; Glycosaminoglycans; Phenotype.

Fig. 1

Patient 1 with severe dysmorphic features. There is bulging of the thoracic cage, hypertolerism, downslanting palpebral fissures, lagophtalmos of the lower eye lids, blue sclerae, a pug nose, low-set and dysplastic ears, corneal clouding [1], generalized cutis laxa [–3], long fingers with campylodactyly and adducted thumbs, broad tips of fingers and toes and bilateral club feet [2, 3]. Perinatal radiography shows osteopenia, multiple fractures, large joint contractures and Wormian bones in the occipital region [4]

Fig. 2

Patient 2 at age 13 yrs. with a disproprionate short stature, genu valgum, a round flat face with midfacial hypoplasia, blue sclerae, downslanting palpebral fissures and prominent eyes [1]. She has long fingers with spatulate distal phalanges and pes planus with hallux valgus [2, 3]. Radiography shows radial head dislocation, short femoral neck, subluxation of the knee joint and irregular tarsal bones [–6]

Fig. 3

a Overview of all the known pathogenic mutations on a schematic representation of the cDNA and gDNA transcript of B3GAT3 on top and a representation of all missense mutations on an in silico model of GlcAT-I in which the substrate donor is colored in dark grey and the substrate acceptor subdomain is colored light grey. All mutations are highlighted in red. b-c In silico modelling. Hydrophilic residues are blue, hydrophobic residues are red. b p.Thr139 (top row) and the p.(Thr139Met) variant (below) with hydrophobicity surface rendering showing a change in the missense variant. The right column shows the disruption of 3 H-bonds in the missense variant. c The p.Gly223 residue (on top) and the p.(Gly223Ser) variant (below) showing the formation of a new H-bond. d Clustal Omega protein sequence aligment showing that the protein sequence of GlcAT-I is (largely) conserved across vertebrates and invertebrates. Asterisks indicate a single, fully conserved residue, colons indicate strong similar properties (> 0.5 on the Gonnet PAM 250 matrix), and periods indicate weak similar properties (< 0.5 in the Gonnet PAM 250 matrix). The sequence alignment shows the high conservation of the Thr residue on position 139 of the sequence (marked in yellow)