Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia
Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia
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DOI：
10.1046/j.1365-2141.2000.02175.x
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发表时间：
2000-08-01
影响因子：
6.5
通讯作者：
von dem Borne, AEGK
中科院分区：
文献类型：
--
作者：
van den Oudenrijn, S;Bruin, M;von dem Borne, AEGK
先天性无巨核细胞性血小板减少症（CAMT）是一种病因不明的罕见疾病。这种疾病表现为严重的血小板减少症和骨髓中缺乏巨核细胞。此外，CAMT患者可能发生骨髓再生障碍性贫血。为了更深入地了解CAMT的机制，对5名儿童进行了分析。所有患者血浆血小板生成素（Tpo）水平升高，表明血小板生成缺陷。在体外液体培养系统中培养来自三名患者的骨髓来源的CD 34（+）干细胞以研究巨核细胞生成。3名患者中有2名患者的CD 34（+）细胞未能分化为巨核细胞。巨核细胞形成的缺乏可能意味着编码Tpo受体的c-mpl基因存在缺陷。c-mpl测序显示5名患者中有4名发生突变。3例患者有c-mpl编码区的点突变和/或缺失。所有的点突变都导致氨基酸替换或提前终止密码子。在一名患者中，发现内含子10的最后一个碱基的纯合突变导致剪接位点的丢失。这项研究表明，c-mpl突变可能是大多数CAMT患者血小板减少的原因。此外，Tpo已被证明对干细胞具有抗凋亡作用。因此，c-mpl的突变可能不仅影响巨核细胞的形成，而且可能损害干细胞的存活，这可以解释骨髓衰竭的发生作为CAMT患者的最终结局。
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder of undefined aetiology. The disease presents with severe thrombocytopenia and absence of megakaryocytes in the bone marrow. Furthermore, CAMT patients may develop bone marrow aplasia. To obtain more insight into the mechanism underlying CAMT, five children were analysed. All patients had increased plasma thrombopoietin (Tpo) levels, indicating a platelet production defect. Bone marrow-derived CD34(+) stem cells from three patients were cultured in an in vitro liquid culture system to study megakaryocytopoiesis. CD34(+) cells from two of the three patients failed to differentiate into megakaryocytes. The lack of megakaryocyte formation could imply that a defect in the c-mpl gene, encoding the Tpo receptor, exists. Sequencing of c-mpl revealed mutations in four of five patients. Three patients had point mutations and/or a deletion in the coding regions of c-mpl. All point mutations led to an amino acid substitution or to a premature stop codon. In one patient, a homozygous mutation in the last base of intron 10 was found that resulted in loss of a splice site. This study showed that mutations in c-mpl could be the cause of thrombocytopenia in CAMT in the majority of patients. Furthermore, Tpo has been shown to have an anti-apoptotic effect on stem cells. Therefore, mutations in c-mpl might not only affect megakaryocyte formation but may also impair stem cell survival, which could explain the occurrence of bone marrow failure as final outcome in patients with CAMT.