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.).
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
阿里巴巴大盗完成签到,获得积分10
2秒前
zying发布了新的文献求助30
2秒前
传奇3应助muzi采纳,获得10
3秒前
3秒前
3秒前
谢琉圭发布了新的文献求助10
5秒前
wu发布了新的文献求助10
6秒前
打滚完成签到,获得积分10
7秒前
LJJ发布了新的文献求助10
7秒前
睡觉了完成签到 ,获得积分10
9秒前
量子星尘发布了新的文献求助10
10秒前
乖猫要努力应助精明寻梅采纳,获得10
10秒前
AI完成签到,获得积分10
13秒前
xiaosu发布了新的文献求助30
14秒前
14秒前
谢琉圭完成签到,获得积分10
16秒前
领导范儿应助稳重的若雁采纳,获得10
19秒前
19秒前
20秒前
wu完成签到,获得积分20
20秒前
momo发布了新的文献求助10
21秒前
22秒前
田様应助123采纳,获得10
22秒前
26秒前
zying完成签到,获得积分10
29秒前
30秒前
双楠应助wangjue采纳,获得10
30秒前
35秒前
雪白尔岚发布了新的文献求助10
39秒前
39秒前
39秒前
慕青应助momo采纳,获得10
40秒前
从容冰夏完成签到,获得积分10
42秒前
42秒前
桐桐应助Candy采纳,获得10
43秒前
YR完成签到,获得积分10
45秒前
欧阳月空发布了新的文献求助10
45秒前
周em12_发布了新的文献求助10
46秒前
糊涂涂完成签到 ,获得积分10
46秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989334
求助须知:如何正确求助?哪些是违规求助? 3531428
关于积分的说明 11253936
捐赠科研通 3270119
什么是DOI,文献DOI怎么找? 1804887
邀请新用户注册赠送积分活动 882087
科研通“疑难数据库(出版商)”最低求助积分说明 809173