PDF(Pubmed)
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.
CONCLUSIONS: This is the first report linking UXS1 to short-limbed short stature in humans.
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.
CONCLUSIONS: This is the first report linking UXS1 to short-limbed short stature in humans.
摘要：
背景:高度糖基化的蛋白聚糖的蛋白质主链中的丝氨酸残基通过四糖接头与糖胺聚糖结合。UXS1编码UDP-葡糖醛酸脱羧酶1，它催化UDP-木糖的合成，连接体中第一个构建块的供体。参与四糖接头形成的其他酶的缺陷会导致所谓的接头病，以身材矮小为特征，尺骨放射状滑膜,骨密度降低，先天性挛缩,位错,还有更多.
方法：对一位轻度骨骼发育不良的父子进行全外显子组测序，以及父亲不受影响的父母。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。使用肝素Red测定和代谢组学研究体内作用。
结果：儿子长骨短，正常骨phy，和微妙的干phy端变化，尤其是在他的腿。在儿子中检测到的可能致病性杂合变体NM_001253875.1（UXS1）：c.557T>Ap。（Ile186Asn）在父亲中是从头。纯化的Ile186Asn-UXS1，与野生型相反，不能将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。
结论：这是第一份将UXS1与人类短肢身材矮小联系起来的报告。
方法：对一位轻度骨骼发育不良的父子进行全外显子组测序，以及父亲不受影响的父母。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。使用肝素Red测定和代谢组学研究体内作用。
结果：儿子长骨短，正常骨phy，和微妙的干phy端变化，尤其是在他的腿。在儿子中检测到的可能致病性杂合变体NM_001253875.1（UXS1）：c.557T>Ap。（Ile186Asn）在父亲中是从头。纯化的Ile186Asn-UXS1，与野生型相反，不能将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。
结论：这是第一份将UXS1与人类短肢身材矮小联系起来的报告。
