IDENTIFICATION OF A NONSENSE MUTATION IN THE GRANULOCYTE-COLONY-STIMULATING FACTOR-RECEPTOR IN SEVERE CONGENITAL NEUTROPENIA
IDENTIFICATION OF A NONSENSE MUTATION IN THE GRANULOCYTE-COLONY-STIMULATING FACTOR-RECEPTOR IN SEVERE CONGENITAL NEUTROPENIA
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DOI：
10.1073/pnas.91.10.4480
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发表时间：
1994-05-10
影响因子：
11.1
通讯作者：
LOWENBERG, B
中科院分区：
文献类型：
--
作者：
DONG, F;HOEFSLOOT, LH;LOWENBERG, B
严重先天性中性粒细胞减少症（Kostmann综合征）的特点是严重的绝对中性粒细胞减少症和早幼粒细胞-髓细胞期骨髓祖细胞成熟阻滞。这类患者的骨髓细胞经常表现出对粒细胞集落刺激因子（G-CSF）的反应性降低。G-CSF结合并激活对粒细胞祖细胞增殖和成熟至关重要的信号转导的特定受体。在这里，我们报告鉴定体细胞点突变的一个等位基因的G-CSF受体基因在患者严重的先天性中性粒细胞减少症。突变导致受体的细胞质截断。当在小鼠髓细胞中表达时，突变受体转导了强烈的生长信号，但与野生型G-CSP受体相比，在成熟诱导方面存在缺陷。突变的受体链可能以显性负性方式阻止粒细胞成熟。
Severe congenital neutropenia (Kostmann syndrome) is characterized by profound absolute neutropenia and a maturation arrest of marrow progenitor cells at the promyelocyte-myelocyte stage. Marrow cells from such patients frequently display a reduced responsiveness to granulocyte colony-stimulating factor (G-CSF). G-CSF binds to and activates a specific receptor which transduces signals critical for the proliferation and maturation of granulocytic progenitor cells. Here we report the identification of a somatic point mutation in one allele of the G-CSF receptor gene in a patient with severe congenital neutropenia. The mutation results in a cytoplasmic truncation of the receptor. When expressed in murine myeloid cells, the mutant receptor transduced a strong growth signal but, in contrast to the wild-type G-CSP receptor, was defective in maturation induction. The mutant receptor chain may act in a dominant negative manner to block granulocytic maturation.