Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency
Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency
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DOI：
10.1182/blood-2016-03-706028
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发表时间：
2016-10-27
期刊：
影响因子：
20.3
通讯作者：
Holland, Steven M.
中科院分区：
文献类型：
--
作者：
Kuhns, Douglas B.;Fink, Danielle L.;Holland, Steven M.
细胞运动、分裂和结构完整性依赖于细胞骨架的动态重塑，而动态重塑部分受到肌动蛋白聚合和解聚的调节。在3个家庭中，我们发现4名儿童患有复发性感染和不同的临床表现，包括轻度中性粒细胞减少症、伤口愈合不良、严重口腔炎伴口腔狭窄和死亡。所有研究的患者都有相似的核叶和胞浆内无颗粒区域的独特的中性粒细胞疝出。趋化性和趋化作用明显受损，但葡萄球菌的杀伤是正常的，中性粒细胞氧化爆发增加的基础和刺激。神经元在玻璃上的扩散和细胞极化也受到损害。神经元F-肌动蛋白升高四倍，表明F-肌动蛋白调节异常。二维差异凝胶电泳确定异常肌动蛋白相互作用蛋白1（Aip 1），编码的WDR 1，在患者样本。在所有患者中鉴定了影响Aip 1的不同反平行β链的WDR 1双等位基因突变。先前已经报道，Aip 1调节cofilin介导的肌动蛋白解聚，这是正常中性粒细胞功能所需的。临床正常亲属的杂合突变证实WDR 1缺乏是常染色体隐性遗传。异基因造血干细胞移植纠正了1例患者的免疫缺陷。WDR 1突变影响中性粒细胞形态、运动和功能，导致一种新的原发性免疫缺陷。
Cell motility, division, and structural integrity depend on dynamic remodeling of the cellular cytoskeleton, which is regulated in part by actin polymerization and depolymerization. In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death. All patients studied had similar distinctive neutrophil herniation of the nuclear lobes and agranular regions within the cytosol. Chemotaxis and chemokinesis were markedly impaired, but staphylococcal killing was normal, and neutrophil oxidative burst was increased both basally and on stimulation. Neutrophil spreading on glass and cell polarization were also impaired. Neutrophil F-actin was elevated fourfold, suggesting an abnormality in F-actin regulation. Two-dimensional differential in-gel electrophoresis identified abnormal actin-interacting protein 1 (Aip1), encoded by WDR1, in patient samples. Biallelic mutations in WDR1 affecting distinct antiparallel beta-strands of Aip1 were identified in all patients. It has been previously reported that Aip1 regulates cofilin-mediated actin depolymerization, which is required for normal neutrophil function. Heterozygous mutations in clinically normal relatives confirmed that WDR1 deficiency is autosomal recessive. Allogeneic stem cell transplantation corrected the immunologic defect in 1 patient. Mutations in WDR1 affect neutrophil morphology, motility, and function, causing a novel primary immunodeficiency.