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Cited by 201Immunodeficiency and Autoimmune DisordersBlood disorders and treatmentsT-cell and B-cell Immunology

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

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Dobbs, Kerry, Domínguez Conde, Cecilia, Zhang, Shen-Ying, Parolini, Silvia, Audry, Magali, Chou, Janet, Haapaniemi, Emma, Keles, Sevgi +41 more·2015·New England Journal of Medicine
DOI 10.1056/nejmoa1413462PMC PMC4480434
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Abstract

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.).

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  • Multiple immunodeficiencies have been linked to DOCK2 mutations.

    “Multiple immunodeficiencies have also been linked to DOCK2 mutations (64).”

    From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [64]

    The Discussion identifies DOCK2 mutations as the cause of a distinctive type of combined immunodeficiency with defects in several aspects of immunity. It does not establish that DOCK2 mutations are linked to multiple distinct immunodeficiency disorders. (LLM, conf=0.85)

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Authors
Dobbs, K., Domínguez Conde, C., Zhang, S.-Y., Parolini, S., Audry, M., Chou, J., Haapaniemi, E., Keles, S., Bilic, I., Okada, S., Massaad, M. J., Rounioja, S., Alwahadneh, A. M., Serwas, N. K., Capuder, K., Çiftçi, E., Felgentreff, K., Ohsumi, T. K., 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, D. B., Parrott, R. E., Savas, B., Schambach, A., Tabellini, G., Bock, C., Chatila, T. A., Comeau, A. M., Geha, R. S., Abel, L., Buckley, R. H., İkincioğulları, A., Al-Herz, W., Helminen, M., Doğu, F., Casanova, J.-L., Boztuğ, K., & Notarangelo, L. D.
Affiliations
  • Boston Children's Hospital (US)
  • Hôpital Necker-Enfants Malades (FR)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2015-06-18
Volume
372
Issue
25
Pages
2409-2422
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1413462
PMC
PMC4480434
OpenAlex
W2153070402
Cited by
201
References
2
Citations by year
2026: 11 · 2025: 13 · 2024: 11 · 2023: 16 · 2022: 18 · 2021: 24 · 2020: 20 · 2019: 22 · 2018: 16 · 2017: 25 · 2016: 17 · 2015: 8
FWCI
10.85
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion, other-oa)
  • eScholarship@UMassChan (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Union Chimique Belge
  • Manton Foundation
  • Deutsche Forschungsgemeinschaft (CRC 738, EXC62/1, Exc-62, REBIRTH / EXC62/1)
  • Austrian Science Fund
  • Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (1059B191300622)
  • National Institutes of Health (UL1TR000043, 1059B191300622)
  • Japan Society for the Promotion of Science (25713039)
  • National Institute of Allergy and Infectious Diseases (R01AI100887)
  • National Center for Research Resources
  • National Center for Advancing Translational Sciences
  • FP7 Ideas: European Research Council (310857)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
combined immunodeficiency, autosomal recessive immunodeficiency, Rac1 activation, T cell dysfunction, NK cell degranulation, lymphopenia, chemokine-induced migration, actin polymerization, interferon alfa-2b, viral replication, allogeneic hematopoietic stem cell transplantation, inherited immunodeficiency
MeSH terms
B-Lymphocytes, Child, Preschool, Female, Genes, Recessive, Humans, Immunologic Deficiency Syndromes, Infant, Killer Cells, Natural, Male, Mutation, Pedigree, T-Lymphocytes, Fatal Outcome, Hematopoietic Stem Cell Transplantation, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, rac1 GTP-Binding Protein, Genetic Diseases, Inborn

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