PUBLICATION
Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency
- Authors
- Block, J., Rashkova, C., Castanon, I., Zoghi, S., Platon, J., Ardy, R.C., Fujiwara, M., Chaves, B., Schoppmeyer, R., van der Made, C.I., Jimenez Heredia, R., Harms, F.L., Alavi, S., Alsina, L., Sanchez Moreno, P., Ávila Polo, R., Cabrera-Pérez, R., Kostel Bal, S., Pfajfer, L., Ransmayr, B., Mautner, A.K., Kondo, R., Tinnacher, A., Caldera, M., Schuster, M., Domínguez Conde, C., Platzer, R., Salzer, E., Boyer, T., Brunner, H.G., Nooitgedagt-Frons, J.E., Iglesias, E., Deyà-Martinez, A., Camacho-Lovillo, M., Menche, J., Bock, C., Huppa, J.B., Pickl, W.F., Distel, M., Yoder, J.A., Traver, D., Engelhardt, K.R., Linden, T., Kager, L., Hannich, J.T., Hoischen, A., Hambleton, S., Illsinger, S., Da Costa, L., Kutsche, K., Chavoshzadeh, Z., van Buul, J.D., Antón, J., Calzada-Hernández, J., Neth, O., Viaud, J., Nishikimi, A., Dupré, L., Boztug, K.
- ID
- ZDB-PUB-230622-41
- Date
- 2023
- Source
- The New England Journal of Medicine 389(6): 527-539 (Journal)
- Registered Authors
- Distel, Martin, Traver, David, Yoder, Jeffrey A.
- Keywords
- none
- MeSH Terms
-
- Actins*/genetics
- Actins*/metabolism
- Anemia*/etiology
- Anemia*/genetics
- Animals
- Disease Models, Animal
- Guanine Nucleotide Exchange Factors*/deficiency
- Guanine Nucleotide Exchange Factors*/genetics
- Hematopoiesis
- Humans
- Inflammation*/etiology
- Inflammation*/genetics
- Mice
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 37342957 Full text @ N. Engl. J. Med.
Citation
Block, J., Rashkova, C., Castanon, I., Zoghi, S., Platon, J., Ardy, R.C., Fujiwara, M., Chaves, B., Schoppmeyer, R., van der Made, C.I., Jimenez Heredia, R., Harms, F.L., Alavi, S., Alsina, L., Sanchez Moreno, P., Ávila Polo, R., Cabrera-Pérez, R., Kostel Bal, S., Pfajfer, L., Ransmayr, B., Mautner, A.K., Kondo, R., Tinnacher, A., Caldera, M., Schuster, M., Domínguez Conde, C., Platzer, R., Salzer, E., Boyer, T., Brunner, H.G., Nooitgedagt-Frons, J.E., Iglesias, E., Deyà-Martinez, A., Camacho-Lovillo, M., Menche, J., Bock, C., Huppa, J.B., Pickl, W.F., Distel, M., Yoder, J.A., Traver, D., Engelhardt, K.R., Linden, T., Kager, L., Hannich, J.T., Hoischen, A., Hambleton, S., Illsinger, S., Da Costa, L., Kutsche, K., Chavoshzadeh, Z., van Buul, J.D., Antón, J., Calzada-Hernández, J., Neth, O., Viaud, J., Nishikimi, A., Dupré, L., Boztug, K. (2023) Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency. The New England Journal of Medicine. 389(6):527-539.
Abstract
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.).
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping