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Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency

免疫学 免疫失调 Wiskott–Aldrich综合征蛋白 Wiskott-Aldrich综合征 生物 免疫系统 单倍率不足 促炎细胞因子 异位表达 细胞生物学 癌症研究 炎症 肌动蛋白细胞骨架 表型 遗传学 细胞骨架 细胞 基因
作者
Jana Block,Christina Rashkova,Irinka Castanon,Samaneh Zoghi,Jessica Platon,Rico Chandra Ardy,M. Fujiwara,Beatriz Chaves,Rouven Schoppmeyer,Caspar I. van der Made,Raúl Jiménez Heredia,Frederike L. Harms,Samin Alavi,Laia Alsina,Paula Sánchez Moreno,Rainiero Ávila Polo,Rocío Cabrera‐Pérez,Sevgi Köstel Bal,Laurène Pfajfer,Bernhard Ransmayr
出处
期刊:The New England Journal of Medicine [Massachusetts Medical Society]
卷期号:389 (6): 527-539 被引量:13
标识
DOI:10.1056/nejmoa2210054
摘要

Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular mechanisms are poorly understood. Dedicator of cytokinesis 11 (DOCK11) activates the small Rho guanosine triphosphatase (GTPase) cell division cycle 42 (CDC42), a central regulator of actin cytoskeleton dynamics. The role of DOCK11 in human immune-cell function and disease remains unknown.We conducted genetic, immunologic, and molecular assays in four patients from four unrelated families who presented with infections, early-onset severe immune dysregulation, normocytic anemia of variable severity associated with anisopoikilocytosis, and developmental delay. Functional assays were performed in patient-derived cells, as well as in mouse and zebrafish models.We identified rare, X-linked germline mutations in DOCK11 in the patients, leading to a loss of protein expression in two patients and impaired CDC42 activation in all four patients. Patient-derived T cells did not form filopodia and showed abnormal migration. In addition, the patient-derived T cells, as well as the T cells from Dock11-knockout mice, showed overt activation and production of proinflammatory cytokines that were associated with an increased degree of nuclear translocation of nuclear factor of activated T cell 1 (NFATc1). Anemia and aberrant erythrocyte morphologic features were recapitulated in a newly generated dock11-knockout zebrafish model, and anemia was amenable to rescue on ectopic expression of constitutively active CDC42.Germline hemizygous loss-of-function mutations affecting the actin regulator DOCK11 were shown to cause a previously unknown inborn error of hematopoiesis and immunity characterized by severe immune dysregulation and systemic inflammation, recurrent infections, and anemia. (Funded by the European Research Council and others.).
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