Centre for Rare Disorders, Oslo University Hospital, Oslo, Norway.
Department of Microbiology, Oslo University Hospital HF, Rikshospitalet, Oslo, Norway.
Mol Genet Genomic Med. 2024 Jun;12(6):e2472. doi: 10.1002/mgg3.2472.
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.
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.
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.
This is the first report linking UXS1 to short-limbed short stature in humans.
高度糖基化蛋白聚糖中蛋白质骨架上的丝氨酸残基通过四糖连接子与糖胺聚糖结合。UXS1 编码 UDP-葡萄糖醛酸脱羧酶 1，它催化 UDP-木糖的合成，这是连接子中第一个构建块的供体。形成四糖连接子的其他酶的缺陷导致所谓的连接子病，其特征是身材矮小、桡尺骨融合、骨密度降低、先天性挛缩、脱位等。
对一名表现出轻度骨骼发育不良的父子以及父亲未受影响的父母进行了全外显子组测序。野生型和突变型 UXS1 在大肠杆菌中重组表达并纯化。通过 LC-MS/MS 评估酶活性。使用 HeparinRed 测定法和代谢组学研究了体内效应。
儿子的长骨短，骨骺正常，下肢干骺端变化细微。在儿子中发现的可能致病的杂合变异体 NM_001253875.1(UXS1):c.557T>A p.(Ile186Asn)是父亲的新生变异。与野生型相比，纯化的 Ile186Asn-UXS1 无法将 UDP-葡萄糖醛酸转化为 UDP-木糖。儿子和父亲的血浆糖胺聚糖水平均降低。
这是首次将 UXS1 与人类短肢短身材联系起来的报道。
