Two new EPO receptor mutations: Truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias
Two new EPO receptor mutations: Truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias
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DOI：
10.1182/blood.v90.5.2057
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发表时间：
1997-09-01
期刊：
影响因子：
20.3
通讯作者：
Prchal, JT
中科院分区：
文献类型：
--
作者：
Kralovics, R;Indrak, K;Prchal, JT
原发性红细胞增多症是由影响造血/红系祖细胞的获得性或先天性突变引起的，其导致对造血细胞因子的异常反应。原发性家族性和先天性红细胞增多症（PFCP;也称为家族性红细胞增多症）的特征在于红细胞质量升高、血清促红细胞生成素（EPO）水平低、血红蛋白的正常氧亲和力和典型的常染色体显性遗传。在这项研究中，我们筛选突变的EPO受体（EPOR;外显子7和8的EPOR基因）在27个无关的受试者与原发性或身份不明的红细胞增多症。发现了两个新的EPOR突变，其导致EPOR截短，类似于先前在PFCP受试者中描述的突变。第一个是在来自俄亥俄州的高加索人家族中发现的7-bp缺失（del 5385 -5991）。第二个突变（5967 insT）是在捷克共和国的一个高加索家庭中发现的。在这两种情况下，检查了受影响受试者红细胞祖细胞的EPO剂量反应，以确认PFCP的诊断。在其中一个家系中，在不添加EPO的含血清培养物中红系祖细胞的体外行为模仿了真性红细胞增多症祖细胞的行为;然而，我们发现抗EPO或抗EPOR的抗体可区分真性红细胞增多症红系祖细胞的体外生长异常与该特定PFCP家族中所见的异常，我们的结论是，PFCP是一种疾病，似乎与EPOR突变的一些家庭。到目前为止，大多数描述的与PFCP相关的EPOR突变（8个中的6个）导致受体的C-末端负调控结构域的缺失，（C）1997由美国血液学学会。
Primary polycythemias are caused by an acquired or inborn mutation affecting hematopoietic/erythroid progenitors that results in an abnormal response to hematopoietic cytokines. Primary familial and congenital polycythemia (PFCP; also known as familial erythrocytosis) is characterized by elevated red blood cell mass, low serum erythropoietin (EPO) level, normal oxygen affinity of hemoglobin, and typically autosomal dominant inheritance. In this study we screened for mutations in the cytoplasmic domain of the EPO receptor (EPOR; exons 7 and 8 of the EPOR gene) in 27 unrelated subjects with primary or unidentified polycythemia. Two new EPOR mutations were found, which lead to truncation of the EPOR similarly to previously described mutations in PFCP subjects, The first is a 7-bp deletion (del5385-5991) found in a Caucasian family from Ohio. The second mutation (5967insT) was found in a Caucasian family from the Czech Republic. In both cases the EPO dose responses of the erythroid progenitors of the affected subjects were examined to confirm the diagnosis of PFCP. In one of these families, the in vitro behavior of erythroid progenitors in serum-containing cultures without the addition of EPO mimicked the behavior of polycythemia vera progenitors; however, we show that antibodies against either EPO or the EPOR distinguish the in vitro growth abnormality of polycythemia vera erythroid progenitors from that seen in this particular PFCP family, We conclude that PFCP is a disorder that appears to be associated in some families with EPOR mutations. So far, most of the described EPOR mutations (6 out of 8) associated with PFCP result in an absence of the C-terminal negative regulatory domain of the receptor, (C) 1997 by The American Society of Hematology.