TY - JOUR
T1 - Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency
AU - Block, Jana
AU - Rashkova, Christina
AU - Castanon, Irinka
AU - Zoghi, Samaneh
AU - Platon, Jessica
AU - Ardy, Rico C
AU - Fujiwara, Mitsuhiro
AU - Chaves, Beatriz
AU - Schoppmeyer, Rouven
AU - van der Made, Caspar I
AU - Jimenez Heredia, Raul
AU - Harms, Frederike L
AU - Alavi, Samin
AU - Alsina, Laia
AU - Sanchez Moreno, Paula
AU - Ávila Polo, Rainiero
AU - Cabrera-Pérez, Rocío
AU - Kostel Bal, Sevgi
AU - Pfajfer, Laurène
AU - Ransmayr, Bernhard
AU - Mautner, Anna-Katharina
AU - Kondo, Ryohei
AU - Tinnacher, Anna
AU - Caldera, Michael
AU - Schuster, Michael
AU - Domínguez Conde, Cecilia
AU - Platzer, René
AU - Salzer, Elisabeth
AU - Boyer, Thomas
AU - Brunner, Han G
AU - Nooitgedagt-Frons, Judith E
AU - Iglesias, Estíbaliz
AU - Deyà-Martinez, Angela
AU - Camacho-Lovillo, Marisol
AU - Menche, Jörg
AU - Bock, Christoph
AU - Huppa, Johannes B
AU - Pickl, Winfried F
AU - Distel, Martin
AU - Yoder, Jeffrey A
AU - Traver, David
AU - Engelhardt, Karin R
AU - Linden, Tobias
AU - Kager, Leo
AU - Hannich, J Thomas
AU - Hoischen, Alexander
AU - Hambleton, Sophie
AU - Illsinger, Sabine
AU - Da Costa, Lydie
AU - Kutsche, Kerstin
AU - Chavoshzadeh, Zahra
AU - van Buul, Jaap D
AU - Antón, Jordi
AU - Calzada-Hernández, Joan
AU - Neth, Olaf
AU - Viaud, Julien
AU - Nishikimi, Akihiko
AU - Dupré, Loïc
AU - Boztug, Kaan
N1 - Publisher Copyright:
© 2023 Massachusetts Medical Society.
PY - 2023/8/10
Y1 - 2023/8/10
N2 - 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.
AB - 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.
KW - Allergy/Immunology
KW - Anemia
KW - Autoimmune Disease
KW - Bone Marrow Transplantation
KW - Dermatology
KW - Dermatology General
KW - Genetics
KW - Genetics General
KW - Hematology/Oncology
KW - Hematology/Oncology General
KW - Immunity
KW - Infectious Disease
KW - Infectious Disease General
KW - Inflammatory Disease
KW - T-Cells
KW - Humans
KW - Inflammation/etiology
KW - Hematopoiesis
KW - Actins/genetics
KW - Disease Models, Animal
KW - Anemia/etiology
KW - Guanine Nucleotide Exchange Factors/deficiency
KW - Zebrafish/genetics
KW - Animals
KW - Mice
UR - http://www.scopus.com/inward/record.url?scp=85169002383&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa2210054
DO - 10.1056/NEJMoa2210054
M3 - Journal article
C2 - 37342957
SN - 0028-4793
VL - 389
SP - 527
EP - 539
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 6
ER -