Mutations affecting the actin regulator WD repeat–containing protein 1 lead to aberrant lymphoid immunity

Background: The actin-interacting protein WD repeat–containing protein 1 (WDR1) promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have been identified recently in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells. Objective: Given the pleiotropic expression of WDR1, here we investigated to what extent it might control the lymphoid arm of the immune system in human subjects. Methods: Histologic and detailed immunologic analyses were performed to elucidate the role of WDR1 in the development and function of B and T lymphocytes. Results: Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis. In addition to defective adhesion and motility of neutrophils and monocytes, WDR1 deficiency was associated with aberrant T-cell activation and B-cell development. T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset. However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation. WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis on B-cell receptor/Toll-like receptor stimulation. Conclusion: Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses

Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency

[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.)Supported by the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (820074, to Dr. Boztug), the Vienna Science and Technology Fund (WWTF-LS16-060, to Drs. Boztug, Dupré, and Menche; WWTFLS14-031, to Drs. Platzer and Huppa), the Deutsche Forschungsgemeinschaft (KU 1240/13-1, to Dr. Kutsche), the Doctoral Fellowship Program of the Austrian Academy of Sciences (25590, to Ms. Block; 24486, to Dr. Ardy), grants from the Centre National de la Recherche Scientifique (International Research Project program, SysTact project, to Dr. Dupré) and Programa Institucional de Internacionalização da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES–PrInt) (to Ms. Chaves), the Wellcome Trust (207556/Z/17/Z, to Dr. Hambleton), the Netherlands Organization for Health Research and Development and the Dutch Research Council (ZonMW NWO Vici grant 91819632, to Drs. van Buul and Schoppmeyer), the Austrian Research Promotion Agency (project 7940628, Danio4Can, to Dr. Distel), a German Academic Exchange Service postdoctoral fellowship and a European Molecular Biology Organization fellowship (to Dr. Distel), and the Research Funding for Longevity Sciences from the National Center for Geriatrics and Gerontology (21-27-2, to Dr. Nishikimi). This study makes use of data shared through the PhenomeCentral repository, funded by Genome Canada and the Canadian Institute of Health Research.Peer reviewe