Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency
Jana Block
(1, 2, 3, 4)
,
Christina Rashkova
(2, 3, 5, 1)
,
Irinka Castanon
(1, 2)
,
Samaneh Zoghi
(2, 3)
,
Jessica Platon
(6, 7)
,
Rico Ardy
(8)
,
Mitsuhiro Fujiwara
(9)
,
Beatriz Chaves
(10, 11)
,
Rouven Schoppmeyer
(12)
,
Caspar van der Made
(13, 14)
,
Raul Jimenez Heredia
(15, 2, 3)
,
Frederike Harms
(16)
,
Samin Alavi
(17)
,
Laia Alsina
(18)
,
Paula Sanchez Moreno
(19)
,
Rainiero Ávila Polo
(19)
,
Rocío Cabrera-Pérez
(15, 2, 3)
,
Sevgi Kostel Bal
(15, 2, 3)
,
Laurène Pfajfer
(10, 2)
,
Bernhard Ransmayr
(15, 2, 3)
,
Anna-Katharina Mautner
(2, 3)
,
Ryohei Kondo
(9)
,
Anna Tinnacher
(3)
,
Michael Caldera
(3)
,
Michael Schuster
(3)
,
Cecilia Domínguez Conde
(2, 3)
,
René Platzer
(4)
,
Elisabeth Salzer
(3, 2, 15)
,
Thomas Boyer
(6, 7)
,
Han Brunner
(20, 13, 21, 22)
,
Judith Nooitgedagt-Frons
(23)
,
Estíbaliz Iglesias
(24)
,
Angela Deyà-Martinez
(24)
,
Marisol Camacho-Lovillo
(3)
,
Jörg Menche
(3)
,
Christoph Bock
(3)
,
Johannes Huppa
(4)
,
Winfried Pickl
(25)
,
Martin Distel
(15)
,
Jeffrey Yoder
(26, 19, 27)
,
David Traver
(28)
,
Karin Engelhardt
(29)
,
Tobias Linden
(30)
,
Leo Kager
(3, 15)
,
J. Thomas Hannich
(3)
,
Alexander Hoischen
(13, 31)
,
Sophie Hambleton
(29)
,
Sabine Illsinger
(30, 32)
,
Lydie Da Costa
(6, 7, 33)
,
Kerstin Kutsche
(16)
,
Zahra Chavoshzadeh
(34)
,
Jaap van Buul
(13)
,
Jordi Antón
(24, 19)
,
Joan Calzada-Hernández
(24)
,
Olaf Neth
(19)
,
Julien Viaud
(35)
,
Akihiko Nishikimi
(9)
,
Loïc Dupré
(3, 10)
,
Kaan Boztug
(1, 2, 3, 5)
1
St. Anna Children’s Cancer Research Institute CCRI [Vienna]
2 LBI-RUD - Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
3 CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria]
4 Institute for Hygiene and Applied Immunology
5 Medizinische Universität Wien = Medical University of Vienna
6 UPJV - Université de Picardie Jules Verne
7 HEMATIM - HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666
8 Pathology Department [Barcelona, Spain]
9 Department of Gastroenterology, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho Obu, Japan
10 Infinity - Institut Toulousain des Maladies Infectieuses et Inflammatoires
11 IOC - Instituto Oswaldo Cruz = Oswaldo Cruz Institute [Rio de Janeiro]
12 Universität des Saarlandes [Saarbrücken] = Saarland University [Saarbrücken]
13 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
14 RadboudUMC - Radboud University Medical Center [Nijmegen]
15 St. Anna Children's Hospital - Saint Anna Children's Hospital [Vienne] = St Anna Kinderspital
16 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
17 Institute for the Health of Women and Children, Gothenburg Paediatric Growth Research Centre (GP-GRC
18 SBUMS - Shahid Beheshti University of Medical Sciences [Tehran]
19 UB - Universitat de Barcelona
20 SILS - Swammerdam Institute for Life Sciences
21 Amsterdam UMC - Amsterdam University Medical Centers
22 Maastricht UMC+ - Maastricht University Medical Center+
23 Slingeland Hospital
24 Institut de Recerca Pediàtrica Hospital Sant Joan de Déu [Barcelona, Spain]
25 LUDWIK HIRSZFELD INSTITUTE OF IMMUNOLOGY AND EXPERIMENTAL THERAPY - Ludwik Hirszfeld Institute of Immunology and Experimental therapy
26 Hospital Sant Joan de Déu [Barcelona]
27 NC State - North Carolina State University [Raleigh]
28 UC San Diego - University of California [San Diego]
29 Newcastle University [Newcastle]
30 University of Oldenburg
31 Radboud University [Nijmegen]
32 MHH - Medizinische Hochschule Hannover = Hannover Medical School
33 Hôpital Robert Debré
34 Mofid Children's Hospital [Téhéran, Iran]
35 UPS/Inserm U1297 - I2MC - Institut des Maladies Métaboliques et Casdiovasculaires
2 LBI-RUD - Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
3 CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria]
4 Institute for Hygiene and Applied Immunology
5 Medizinische Universität Wien = Medical University of Vienna
6 UPJV - Université de Picardie Jules Verne
7 HEMATIM - HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666
8 Pathology Department [Barcelona, Spain]
9 Department of Gastroenterology, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho Obu, Japan
10 Infinity - Institut Toulousain des Maladies Infectieuses et Inflammatoires
11 IOC - Instituto Oswaldo Cruz = Oswaldo Cruz Institute [Rio de Janeiro]
12 Universität des Saarlandes [Saarbrücken] = Saarland University [Saarbrücken]
13 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
14 RadboudUMC - Radboud University Medical Center [Nijmegen]
15 St. Anna Children's Hospital - Saint Anna Children's Hospital [Vienne] = St Anna Kinderspital
16 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
17 Institute for the Health of Women and Children, Gothenburg Paediatric Growth Research Centre (GP-GRC
18 SBUMS - Shahid Beheshti University of Medical Sciences [Tehran]
19 UB - Universitat de Barcelona
20 SILS - Swammerdam Institute for Life Sciences
21 Amsterdam UMC - Amsterdam University Medical Centers
22 Maastricht UMC+ - Maastricht University Medical Center+
23 Slingeland Hospital
24 Institut de Recerca Pediàtrica Hospital Sant Joan de Déu [Barcelona, Spain]
25 LUDWIK HIRSZFELD INSTITUTE OF IMMUNOLOGY AND EXPERIMENTAL THERAPY - Ludwik Hirszfeld Institute of Immunology and Experimental therapy
26 Hospital Sant Joan de Déu [Barcelona]
27 NC State - North Carolina State University [Raleigh]
28 UC San Diego - University of California [San Diego]
29 Newcastle University [Newcastle]
30 University of Oldenburg
31 Radboud University [Nijmegen]
32 MHH - Medizinische Hochschule Hannover = Hannover Medical School
33 Hôpital Robert Debré
34 Mofid Children's Hospital [Téhéran, Iran]
35 UPS/Inserm U1297 - I2MC - Institut des Maladies Métaboliques et Casdiovasculaires
Christina Rashkova
- Fonction : Auteur
Caspar van der Made
- Fonction : Auteur
- PersonId : 1264099
- ORCID : 0000-0003-0763-4017
Kaan Boztug
- Fonction : Auteur
Résumé
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.).