A monoallelic UXS1 variant associated with short-limbed short stature

Mol Genet Genomic Med. 2024 Jun;12(6):e2472. doi: 10.1002/mgg3.2472.


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.

Keywords: medical genetics; monogenic disorder; skeletal dysplasia.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Alleles
  • Carboxy-Lyases / genetics
  • Carboxy-Lyases / metabolism
  • Dwarfism* / genetics
  • Dwarfism* / metabolism
  • Dwarfism* / pathology
  • Humans
  • Male
  • Mutation
  • Pedigree
  • Phenotype


  • Carboxy-Lyases