首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene
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Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene

机译:C1galt1基因突变的小鼠的血小板减少症和肾脏疾病

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An N-ethyl-N-nitrosourea mutagenesis screen in mice was performed to isolate regulators of circulating platelet number. We report here recessive thrombocytopenia and kidney disease in plt1 mice, which is the result of a severe but partial loss-of-function mutation in the gene encoding glycoprotein-N-acetylgalactosamine-3-beta-galactosyltransferase (C1GalT1), an enzyme essential for the synthesis of extended mucin-type O-glycans. Platelet half-life and basic hemostatic parameters were unaffected in plt1/plt1 mice, and the thrombocytopenia and kidney disease were not attenuated on a lymphocyte-deficient rag1-null background. underglycosylated proteins in plt1/plt1 platelets and the kidney, respectively, implying that these are key targets for ClGaIT1, appropriate glycosylation of which is essential for platelet production and kidney function. Compromised ClGaIT1 activity has been associated with immune-mediated diseases in humans, most notably Tin syndrome and IgA nephropathy. The disease in plt1/plt1 mice suggests that, in addition to immune-mediated effects, intrinsic C1Gal-T1 deficiency in megakaryocytes and the kidney may contribute to pathology.
机译:进行了小鼠N-乙基-N-亚硝基脲诱变筛选,以分离循环血小板数的调节剂。我们在这里报告了plt1小鼠的隐性血小板减少症和肾脏疾病,这是编码糖蛋白-N-乙酰半乳糖胺-3-β-半乳糖基转移酶(C1GalT1)的基因中严重但部分功能丧失的突变的结果延伸的粘蛋白型O-聚糖的合成。 plt1 / plt1小鼠的血小板半衰期和基本止血参数不受影响,并且在缺乏淋巴细胞的rag1-null背景下,血小板减少症和肾脏疾病并未减弱。分别在plt1 / plt1血小板和肾脏中的糖基化不足的蛋白质,表明它们是ClGaIT1的关键靶标,ClGaIT1的适当糖基化对于血小板生成和肾功能至关重要。 ClGaIT1活性下降与人类免疫介导的疾病有关,最明显的是锡综合征和IgA肾病。 plt1 / plt1小鼠的疾病表明,除了免疫介导的作用外,巨核细胞和肾脏中固有的C1Gal-T1缺乏症也可能导致病理。

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