A monoallelic UXS1 variant associated with short‐limbed short stature

Background Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes UDP‐glucuronate decarboxylase 1, which catalyzes synthesis of UDP‐xylose, the donor of the first building block in the linker. Defects in other enzymes involved in formation of the tetrasaccharide linker cause so‐called linkeropathies, characterized by short stature, radio‐ulnar synostosis, decreased bone density, congenital contractures, dislocations, and more. Methods Whole exome sequencing was performed in a father and son who presented with a mild skeletal dysplasia, as well as the father's unaffected parents. Wild‐type and mutant UXS1 were recombinantly expressed in Escherichia coli and purified. Enzyme activity was evaluated by LC–MS/MS. In vivo effects were studied using HeparinRed assay and metabolomics. Results The son had short long bones, normal epiphysis, and subtle metaphyseal changes especially in his legs. The likely pathogenic heterozygous variant NM_001253875.1(UXS1):c.557T>A p.(Ile186Asn) detected in the son was de novo in the father. Purified Ile186Asn‐UXS1, in contrast to the wild‐type, was not able to convert UDP‐glucuronic acid to UDP‐xylose. Plasma glycosaminoglycan levels were decreased in both son and father. Conclusion This is the first report linking UXS1 to short‐limbed short stature in humans. This is the first described family where a likely pathogenic variant in UXS1 causes short stature and metaphyseal changes through impaired glycosaminoglycan biosynthesis.