Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency

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 RansmayrAnna-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, Kaan Boztug

Research output: Journal article (peer-reviewed)Journal article

6 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)527-539
Number of pages13
JournalNew England Journal of Medicine
Issue number6
Early online date21 Jun 2023
Publication statusPublished - 10 Aug 2023


  • Allergy/Immunology
  • Anemia
  • Autoimmune Disease
  • Bone Marrow Transplantation
  • Dermatology
  • Dermatology General
  • Genetics
  • Genetics General
  • Hematology/Oncology
  • Hematology/Oncology General
  • Immunity
  • Infectious Disease
  • Infectious Disease General
  • Inflammatory Disease
  • T-Cells
  • Humans
  • Inflammation/etiology
  • Hematopoiesis
  • Actins/genetics
  • Disease Models, Animal
  • Anemia/etiology
  • Guanine Nucleotide Exchange Factors/deficiency
  • Zebrafish/genetics
  • Animals
  • Mice

ASJC Scopus subject areas

  • General Medicine


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