| Author | Block, Jana | |
| Author | Rashkova, Christina | |
| Author | Castanon, Irinka | |
| Author | Zoghi, Samaneh | |
| Author | Platon, Jessica | |
| Author | Ardy, Rico C. | |
| Author | Fujiwara, Mitsuhiro | |
| Author | Chaves, Beatriz | |
| Author | Schoppmeyer, Rouven | |
| Author | Made, Caspar I. van der | |
| Author | Jimenez Heredia, Raul | |
| Access date | 2024-03-14T14:11:21Z | |
| Available date | 2024-03-14T14:11:21Z | |
| Document date | 2022 | |
| Citation | BLOCK, Jana et al. Systemic inflammation and normocytic anemia in DOCK11 deficiency. New England Journal of Medicine, v. 389, n. 6, p. 527-539, 10 Aug. 2023. | |
| ISSN | 0028-4793 | en_US |
| URI | https://www.arca.fiocruz.br/handle/icict/63042 | |
| Sponsorship | This work was supported by PAEF-Fiocruz e Programa Jovem Cientista do Nosso Estado - Faperj (E-26/202.760/2019). | en_US |
| Language | eng | en_US |
| Publisher | Massachusetts Medical Society | en_US |
| Rights | restricted access | |
| Title | Systemic inflammation and normocytic anemia in DOCK11 deficiency | en_US |
| Type | Article | |
| DOI | 10.1056/NEJMoa2210054 | |
| 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 patientderived 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. | en_US |
| Affilliation | St. Anna Children's Cancer Research Institute. Vienna, Austria. | |
| Affilliation | St. Anna Children's Cancer Research Institute. Vienna, Austria. | |
| Affilliation | St. Anna Children's Cancer Research Institute. Vienna, Austria. | |
| Affilliation | St. Anna Children's Cancer Research Institute. Vienna, Austria. | |
| Affilliation | Université de Picardie Jules Verne. Amiens, France. | |
| Affilliation | St. Anna Children's Cancer Research Institute. Vienna, Austria / Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases. Vienna, Austria / CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Vienna, Austria. | |
| Affilliation | National Center for Geriatrics and Gerontology. Research Institute. Obu, Japan. | |
| Affilliation | Centre national de la recherche scientifique. Paris, France / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Fiocruz Ceará. Eusébio, CE, Brasil. | |
| Affilliation | Sanquin Research. Department of Molecular Hematology. The Molecular Cell Biology Lab. Amsterdam, Netherlands / Amsterdam University Medical Center. Department of Medical Biochemistry. The Vascular Cell Biology Lab. Amsterdam, Netherlands / University of Amsterdam. Leeuwenhoek Center for Advanced Microscopy. Section of Molecular Cytology. Amsterdam, Netherlands / University of Amsterdam. Swammerdam Institute for Life Sciences. Amsterdam, Netherlands. | |
| Affilliation | Radboud University Medical Center. Department of Human Genetics. Nijmegen, Netherlands / Radboud University Medical Center for Infectious Diseases. Department of Internal Medicine. Nijmegen, Netherlands. | |
| Affilliation | St. Anna Children's Cancer Research Institute. Vienna, Austria / Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases. Vienna, Austria / CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Vienna, Austria. | |
| Subject | Dedicator of cytokinesis 11 (DOCK11) | en_US |
| Subject | Rho guanosine triphosphatase (GTPase) | en_US |
| Subject | Cell division cycle 42 (CDC42) | en_US |
| Subject | Severe immune dysregulation | en_US |
| Subject | Normocytic anemia | en_US |
| Subject | Anisopoikilocytosis | en_US |
| Subject | Developmental delay | en_US |
| e-ISSN | 1533-4406 | |
| Embargo date | 2030-12-31 | |
