• Jana Block, Christina Rashkova, Irinka Castanon, Samaneh Zoghi, Jessica Platon, Rico C Ardy, Mitsuhiro Fujiwara, Beatriz Chaves, Rouven Schoppmeyer, Caspar I van der Made, Raul Jimenez Heredia, Frederike L Harms, Samin Alavi, Laia Alsina, Paula Sanchez Moreno, Rainiero Ávila Polo, Rocío Cabrera-Pérez, Sevgi Kostel Bal, Laurène Pfajfer, Bernhard Ransmayr, Anna-Katharina Mautner, Ryohei Kondo, Anna Tinnacher, Michael Caldera, Michael Schuster, Cecilia Domínguez Conde, René Platzer, Elisabeth Salzer, Thomas Boyer, Han G Brunner, Judith E Nooitgedagt-Frons, Estíbaliz Iglesias, Angela Deyà-Martinez, Marisol Camacho-Lovillo, Jörg Menche, Christoph Bock, Johannes B Huppa, Winfried F Pickl, Martin Distel, Jeffrey A Yoder, David Traver, Karin R Engelhardt, Tobias Linden, Leo Kager, J Thomas Hannich, Alexander Hoischen, Sophie Hambleton, Sabine Illsinger, Lydie Da Costa, Kerstin Kutsche, Zahra Chavoshzadeh, Jaap D van Buul, Jordi Antón, Joan Calzada-Hernández, Olaf Neth, Julien Viaud, Akihiko Nishikimi, Loïc Dupré, and Kaan Boztug.
• From St. Anna Children's Cancer Research Institute (CCRI) (J.B., C.R., I.C., S.Z., R.C.A., R.J.H., S.K.B., B.R., E.S., M.D., L.K., K.B.), the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (J.B., C.R., I.C., S.Z., R.C.A., R.J.H., S.K.B., L.P., B.R., A.-K.M., C.D.C., E.S., C.B., L.D., K.B.), CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (J.B., C.R., S.Z., R.C.A., R.J.H., S.K.B., B.R., A.T., M.C., M.S., C.D.C., E.S., J.M., C.B., J.T.H., K.B.), and the Departments of Pediatrics and Adolescent Medicine (C.R., R.J.H., E.S., L.K., K.B.) and Dermatology (A.-K.M., L.D.), the Institute for Hygiene and Applied Immunology (R.P., J.B.H.) and the Institute of Immunology (W.F.P.), Center for Pathophysiology, Infectiology, and Immunology, and the Institute of Artificial Intelligence, Center for Medical Data Science (C.B.), Medical University of Vienna, the St. Anna Children's Hospital (E.S., L.K., K.B.), the Department of Structural and Computational Biology, Max Perutz Labs, and the Faculty of Mathematics, University of Vienna (J.M.), Vienna, and the Karl Landsteiner University of Health Sciences, Krems (W.F.P.) - all in Austria; Hématopoïèse et Immunologie (HEMATIM) Unité de Recherche 4666, Université de Picardie Jules Verne (J.P., T.B., L.D.C.), and Service d'Hématologie Biologique (Hematology Diagnostic Lab), Centre Hospitalier Universitaire d'Amiens (T.B.), Amiens, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM and Paul Sabatier University (Unité Mixte de Recherche 1291), and Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5051) (B.C., L.P., L.D.), and the Institute of Cardiovascular and Metabolic Diseases (I2MC), INSERM and Paul Sabatier University (Unité Mixte de Recherche 1297) (J.V.), Toulouse, and Service d'Hématologie Biologique (Hematology Diagnostic Lab), Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, the University of Paris, and the Laboratory of Excellence for Red Cells, Laboratory of Excellence GR-Ex, Paris (L.D.C.) - all in France; the Biosafety Division, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan (M.F., R.K., A.N.); the National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, and the Computational Modeling Group, Oswaldo Cruz Foundation (Fiocruz), Eusébio - both in Brazil (B.C.); the Molecular Cell Biology Lab, Department of Molecular Hematology, Sanquin Research, the Vascular Cell Biology Lab, Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam, and the Leeuwenhoek Center for Advanced Microscopy, Section of Molecular Cytology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam (R.S., J.D.B.), the Department of Human Genetics (C.I.M., H.G.B., A.H.) and the Radboud University Medical Center for Infectious Diseases, Department of Internal Medicine, Radboud University Medical Center, Nijmegen (C.I.M., A.H.), the Department of Clinical Genetics, Maastricht University Medical Center, and GROW School for Oncology and Reproduction, Maastricht University, Maastricht (H.G.B.), and the Department of Pediatrics, Slingeland Hospital, Doetinchem (J.E.N.-F.) - all in the Netherlands; the Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg (F.L.H., K.K.), University Children's Hospital Oldenburg, Department of Neuropediatrics, Oldenburg (T.L., S.I.), and the Center for Pediatrics and Adolescent Medicine, Department of Pediatric Kidney, Liver, and Metabolic Diseases and Neuropediatrics, Hannover Medical School, Hannover (S.I.) - all in Germany; the Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children's Health (S.A.), and the Allergy and Clinical Immunology Department, Mofid Children's Hospital (Z.C.), Shahid Beheshti University of Medical Sciences, Tehran, Iran; the Clinical Immunology and Primary Immunodeficiencies Unit, Allergy and Clinical Immunology Department (L.A., A.D.-M.), and the Pediatric Rheumatology Department (E.I., J.A., J.C.-H.), Hospital Sant Joan de Déu, the Study Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu (L.A., E.I., A.D.-M., J.A., J.C.-H.), and the Department of Surgery and Surgical Specializations, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (L.A., J.A.), Barcelona, and the Pediatric Infectious Diseases, Rheumatology, and Immunology Unit (P.S.M., M.C.-L., O.N.) and the Department of Pathology (R.Á.P., R.C.-P.), Hospital Universitario Virgen del Rocío, Institute of Biomedicine of Seville, Seville - all in Spain; the Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh (J.A.Y.); the Department of Cellular and Molecular Medicine and the Section of Cell and Developmental Biology, University of California, San Diego, La Jolla (D.T.); and the Primary Immunodeficiency Group, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (K.R.E., S.H.).
• N. Engl. J. Med. 2023 Aug 10; 389 (6): 527539527-539.

BackgroundIncreasing 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.MethodsWe 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.ResultsWe 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.ConclusionsGermline 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.).Copyright © 2023 Massachusetts Medical Society.

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