Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation
Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation
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DOI：
10.1073/pnas.080074897
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发表时间：
2000-04-25
影响因子：
11.1
通讯作者：
Roos, D
中科院分区：
文献类型：
--
作者：
Ambruso, DR;Knall, C;Roos, D
一个5周大的男婴表现出严重的细菌感染和伤口愈合不良，提示中性粒细胞缺陷。该患者的中性粒细胞趋化性降低。极化、亲氮颗粒分泌和超氧阴离子（O-2(-)）产生，但CD11b表达正常和上调。Rac2在中性粒细胞中占Rac的96%，是gtpase Rho家族的一员，调节肌动蛋白细胞骨架和O-2（-）的产生。患者中性粒细胞裂解物的Western blot分析显示，Rac2蛋白水平降低。在体外测定系统中，将重组Rac添加到患者中性粒细胞的提取物中重建O-2（-）的生产。分子分析发现，在Rac2基因的一个等位基因上发生点突变，导致Asp57被Asn （Rac2 (D57N)）取代。Asp57在所有已定义的gtp结合蛋白中都是不变的。RaC2（D57N）结合GDP而不结合GTP，并抑制氧化酶的激活和O-2（-）的产生。这些数据代表了与人类免疫缺陷综合征相关的GTPases Rho家族成员的抑制性突变的描述。
A 5-week-old male infant presented with severe bacterial infections and poor wound healing, suggesting a neutrophil defect. Neutrophils from this patient exhibited decreased chemotaxis. polarization, azurophilic granule secretion, and superoxide anion (O-2(-)) production but had normal expression and up-regulation of CD11b. Rac2, which constitutes >96% of the Rac in neutrophils, is a member of the Rho family of GTPases that regulates the actin cytoskeleton and O-2(-) production. Western blot analysis of lysates from patient neutrophils demonstrated decreased levels of Rac2 protein. Addition of recombinant Rac to extracts of the patient neutrophils reconstituted O-2(-) production in an in vitro assay system. Molecular analysis identified a point mutation in one allele of the Rac2 gene resulting in the substitution of Asp57 by an Asn (RaC2(D57N)). Asp57 is invariant in all defined GTP-binding proteins. RaC2(D57N) binds GDP but not GTP and inhibits oxidase activation and O-2(-) production in vitro. These data represent the description of an inhibitory mutation in a member of the Rho family of GTPases associated with a human immunodeficiency syndrome.