B3gat3-KO Mouse

B3gat3, encoding β-1,3-glucuronyltransferase 3, is involved in the linkage process of glycosaminoglycan (GAG) to the core protein to form functional proteoglycans (PGs), which are crucial for connective tissue constitution and function [1,3,4]. The normal GAG side-chain composition determined by B3gat3-mediated linkage is related to a wide range of biological events [1].

Mutations in B3gat3 lead to linkeropathies, a group of multisystem disorders. A 22-year-old female patient with a novel in-frame deletion in B3gat3 (c.61_63delCTC (p.(Leu21del))) presented with congenital severe joint malalignment, hypermobility, kyphoscoliosis, osteoporosis, diaphragmatic hernia, dental anomalies, digital malformations, and characteristic facial features [1]. A Chinese infant with two heterozygous B3gat3 variants (c.752T>C, p.V251A and c.47C>A, p.S16*) showed severe phenotypes including joint dislocation, cranial dysplasia, and aortic root dilation [2]. In a review of 23 patients from 10 families with bi-allelic mutations and one with a heterozygous splice-site mutation in B3GAT3, phenotypes such as skeletal dysplasia, facial dysmorphology, and spatulate distal phalanges were common, with more variable cardiac defects, joint hypermobility, dislocations/contractures, and fractures [3]. Some genotype-phenotype correlations emerged, with more severe phenotypes associated with mutations in the substrate acceptor subdomain of the catalytic domain [3]. Six patients from four consanguineous families with a unique homozygous mutation (c.667G>A, p.Gly223Ser) in B3GAT3 had craniosynostosis, midface hypoplasia, radioulnar synostosis, multiple neonatal fractures, dislocated joints, and cardiovascular abnormalities, and all died before 1 year of age [5].

In conclusion, B3gat3 is essential for the synthesis of functional proteoglycans in connective tissues. Research on B3gat3-related mutations in patients has revealed its role in linkeropathies, which present with a complex and variable set of phenotypes including skeletal, facial, cardiac, and joint-related abnormalities. Understanding B3gat3's function through these patient-based studies provides insights into the molecular mechanisms underlying these rare connective tissue disorders.