Identification of MPL R102P Mutation in Hereditary Thrombocytosis.
Identification of MPL R102P Mutation in Hereditary Thrombocytosis.
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遗传性血小板增多症中 MPL R102P 突变的鉴定。
DOI：
10.3389/fendo.2017.00235
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发表时间：
2017
影响因子：
5.2
通讯作者：
Plo I
中科院分区：
文献类型：
--
作者：
Bellanné-Chantelot C;Mosca M;Marty C;Favier R;Vainchenker W;Plo I
遗传性血小板增多症的分子基础是影响血小板生成素（TPO）/TPO受体（MPL）/JAK 2信号传导轴的种系突变。在这里，我们报告一个家庭提出了两个案件与轻度血小板增多症。通过对JAK 2和MPL编码外显子进行测序，我们在先证者及其女儿中发现了一个生殖系MPL R102 P杂合突变。同时，我们在这两名患者的血清中检测到高TPO水平。该突变未发现在其他三个未受影响的情况下，从家庭，除了在另一个先证者的女儿谁没有血小板增多症，但有一个高TPO水平。MPL R102 P突变首先在先天性无巨核细胞性血小板减少症中被描述为纯合子状态，具有功能丧失活性。先前显示，MPL R102 P在内质网中被阻断而不能易位到质膜。因此，该病例报告首次确定MPL R102 P突变可以不同地影响巨核细胞生成：血小板增多或血小板减少，分别取决于杂合或纯合状态的存在。与杂合子MPL R102 P相关的矛盾效应可能是由于血小板中野生型MPL的细胞表面表达低于正常水平诱导TPO清除缺陷。因此，增加的TPO水平可激活表达较低但仍足够水平的MPL以诱导增殖的巨核细胞祖细胞。
The molecular basis of hereditary thrombocytosis is germline mutations affecting the thrombopoietin (TPO)/TPO receptor (MPL)/JAK2 signaling axis. Here, we report one family presenting two cases with a mild thrombocytosis. By sequencing JAK2 and MPL coding exons, we identified a germline MPL R102P heterozygous mutation in the proband and his daughter. Concomitantly, we detected high TPO levels in the serum of these two patients. The mutation was not found in three other unaffected cases from the family except in another proband’s daughter who did not present thrombocytosis but had a high TPO level. The MPL R102P mutation was first described in congenital amegakaryocytic thrombocytopenia in a homozygous state with a loss-of-function activity. It was previously shown that MPL R102P was blocked in the endoplasmic reticulum without being able to translocate to the plasma membrane. Thus, this case report identifies for the first time that MPL R102P mutation can differently impact megakaryopoiesis: thrombocytosis or thrombocytopenia depending on the presence of the heterozygous or homozygous state, respectively. The paradoxical effect associated with heterozygous MPL R102P may be due to subnormal cell-surface expression of wild-type MPL in platelets inducing a defective TPO clearance. As a consequence, increased TPO levels may activate megakaryocyte progenitors that express a lower, but still sufficient level of MPL for the induction of proliferation.
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影响因子：
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