Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.

Published

Journal Article

Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).

Full Text

Duke Authors

Cited Authors

  • Dobbs, K; Domínguez Conde, C; Zhang, S-Y; Parolini, S; Audry, M; Chou, J; Haapaniemi, E; Keles, S; Bilic, I; Okada, S; Massaad, MJ; Rounioja, S; Alwahadneh, AM; Serwas, NK; Capuder, K; Çiftçi, E; Felgentreff, K; Ohsumi, TK; Pedergnana, V; Boisson, B; Haskoloğlu, Ş; Ensari, A; Schuster, M; Moretta, A; Itan, Y; Patrizi, O; Rozenberg, F; Lebon, P; Saarela, J; Knip, M; Petrovski, S; Goldstein, DB; Parrott, RE; Savas, B; Schambach, A; Tabellini, G; Bock, C; Chatila, TA; Comeau, AM; Geha, RS; Abel, L; Buckley, RH; İkincioğulları, A; Al-Herz, W; Helminen, M; Doğu, F; Casanova, J-L; Boztuğ, K; Notarangelo, LD

Published Date

  • June 2015

Published In

Volume / Issue

  • 372 / 25

Start / End Page

  • 2409 - 2422

PubMed ID

  • 26083206

Pubmed Central ID

  • 26083206

Electronic International Standard Serial Number (EISSN)

  • 1533-4406

International Standard Serial Number (ISSN)

  • 0028-4793

Digital Object Identifier (DOI)

  • 10.1056/NEJMoa1413462

Language

  • eng