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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mpl Baltimore: A thrombopoietin receptor polymorphism associated with thrombocytosis.
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Mpl Baltimore: A thrombopoietin receptor polymorphism associated with thrombocytosis.

机译：Mpl Baltimore：与血小板增多症相关的血小板生成素受体多态性。

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摘要

The chronic myeloproliferative disorders (MPD) are clonal hematopoietic stem cell disorders of unknown etiology. We have reported defective thrombopoietin receptor (Mpl) protein expression in MPD patients. To determine whether the basis of abnormal Mpl protein expression was due to mutations in the Mpl gene, we sequenced Mpl cDNA from MPD patients. We found a single nucleotide substitution (G1238T) that results in a change from lysine to asparagine at amino acid 39 (K39N) in three African-American women referred for an evaluation of an MPD. We subsequently screened more than 400 patients and controls and found that the K39N substitution is a polymorphism restricted to African Americans and that approximately 7% of African Americans are heterozygous for K39N. African Americans with the K39N polymorphism had a significantly higher platelet count than controls without the polymorphism (P < 0.001) and reduced platelet protein Mpl expression. Expression of an Mpl cDNA containing the K39N substitution in cell lines was associated with incomplete processing and a reduction in Mpl protein, recapitulating the Mpl protein defect observed in platelets from individuals with K39N. K39N represents an identified functional Mpl polymorphism and is associated with altered protein expression of Mpl and a clinical phenotype of thrombocytosis.
机译：慢性骨髓增生性疾病（MPD）是病因不明的克隆性造血干细胞疾病。我们已经报告了MPD患者中血小板生成素受体（Mpl）蛋白表达缺陷。为了确定异常Mpl蛋白表达的基础是否是由于Mpl基因突变引起的，我们对来自MPD患者的Mpl cDNA进行了测序。我们发现了一个单核苷酸取代（G1238T），导致三名被推荐评估MPD的非裔美国女性从39位赖氨酸变为天冬酰胺（K39N）。随后，我们筛选了400多名患者和对照，发现K39N取代是一种仅限于非裔美国人的多态性，大约7％的非洲裔美国人是K39N的杂合子。具有K39N多态性的非裔美国人的血小板计数明显高于没有多态性的对照（P <0.001）和血小板蛋白Mpl表达降低。在细胞系中含有K39N取代的Mpl cDNA的表达与不完全加工和Mpl蛋白的减少有关，概括了在患有K39N的个体的血小板中观察到的Mpl蛋白缺陷。 K39N代表已鉴定的功能性Mpl多态性，并与Mpl的蛋白表达改变和血小板增多症的临床表型有关。

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