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Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency.

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  • 1From 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; 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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.).

The New England Journal of Medicine
|June 21, 2023
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Genetic defects in Dedicator of cytokinesis 11 (DOCK11) cause a new immune disorder. This actin regulator

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Area of Science:

  • Immunology
  • Genetics
  • Cell Biology

Background:

  • Genetic defects in actin-regulatory proteins are linked to severe autoimmune and autoinflammatory diseases.
  • Dedicator of cytokinesis 11 (DOCK11) activates cell division cycle 42 (CDC42), a key regulator of actin dynamics.
  • The role of DOCK11 in human immune cells and disease is currently unknown.

Purpose of the Study:

  • Investigate the role of DOCK11 in human immune-cell function and disease.
  • Identify the molecular mechanisms underlying severe autoimmunity and autoinflammation linked to actin-regulatory protein defects.

Main Methods:

  • Genetic, immunologic, and molecular assays were performed on four patients from unrelated families.
  • Functional assays utilized patient-derived cells and mouse/zebrafish models.
  • Analysis included genetic mutation identification, protein expression, CDC42 activation, cell migration, cytokine production, and anemia assessment.

Main Results:

  • Rare, X-linked germline mutations in DOCK11 were identified, causing loss of protein expression or impaired CDC42 activation.
  • Patient T cells exhibited defective filopodia formation, abnormal migration, and heightened activation with pro-inflammatory cytokine production.
  • A DOCK11-knockout zebrafish model recapitulated anemia and aberrant erythrocyte morphology, which was rescued by active CDC42.

Conclusions:

  • Germline loss-of-function mutations in DOCK11 cause a novel inborn error of hematopoiesis and immunity.
  • This disorder is characterized by severe immune dysregulation, systemic inflammation, recurrent infections, and anemia.
  • DOCK11 is crucial for normal immune-cell function and hematopoiesis.