A monoallelic UXS1 variant associated with short-limbed short stature.
Mol Genet Genomic Med
; 12(6): e2472, 2024 Jun.
Article
in En
| MEDLINE
| ID: mdl-38860481
ABSTRACT
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.Key words
Full text:
1
Database:
MEDLINE
Main subject:
Dwarfism
Limits:
Adult
/
Humans
/
Male
Language:
En
Journal:
Mol Genet Genomic Med
Year:
2024
Type:
Article
Affiliation country:
Norway