Mpl Baltimore: A thrombopoietin receptor polymorphism associated with thrombocytosis
Mpl Baltimore: A thrombopoietin receptor polymorphism associated with thrombocytosis
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DOI：
10.1073/pnas.0404241101
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发表时间：
2004-08-03
影响因子：
11.1
通讯作者：
Spivak, JL
中科院分区：
文献类型：
--
作者：
Moliterno, AR;Williams, DM;Spivak, JL
慢性骨髓增生性疾病（MPD）是一种病因不明的克隆性造血干细胞疾病。我们报道了血小板生成素受体（Mpl）蛋白在MPD患者中的表达缺陷。为了确定Mpl蛋白异常表达的基础是否由Mpl基因突变引起，我们对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3名非裔美国妇女在39号氨基酸（K39N）上从赖氨酸转变为天冬酰胺。我们随后筛选了400多名患者和对照组，发现K39N替代是一种仅限于非洲裔美国人的多态性，大约7%的非洲裔美国人是K39N杂合的。具有K39N多态性的非裔美国人血小板计数明显高于无多态性的对照组（P < 0.001），血小板蛋白MpI表达降低。细胞系中含有K39N替代的Mpl cDNA的表达与MpI蛋白的不完全加工和减少有关，概括了在K39N个体的血小板中观察到的MpI蛋白缺陷。K39N代表一种确定的功能性Mpl多态性，与Mpl蛋白表达改变和血小板增多症的临床表型相关。
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 approximate to7% 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 MpI expression. Expression of an Mpl cDNA containing the K39N substitution in cell lines was associated with incomplete processing and a reduction in MpI protein, recapitulating the MpI 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.