Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

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dc.contributor.authorDobbs, K.
dc.contributor.authorConde, C. Dominguez
dc.contributor.authorZhang, S. -Y.
dc.contributor.authorParolini, S.
dc.contributor.authorAudry, M.
dc.contributor.authorChou, J.
dc.contributor.authorHaapaniemi, E.
dc.date.accessioned2024-02-23T14:17:03Z
dc.date.available2024-02-23T14:17:03Z
dc.date.issued2015
dc.departmentNEÜen_US
dc.description.abstractBACKGROUND 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, auto-immunity, 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-a and interferon-lambda 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.en_US
dc.description.sponsorshipNational Institutes of Health; Grants-in-Aid for Scientific Research [25713039] Funding Source: KAKEN; Austrian Science Fund (FWF) [Y 595] Funding Source: researchfishen_US
dc.description.sponsorshipSupported by the National Institutes of Health and others.en_US
dc.identifier.doi10.1056/NEJMoa1413462
dc.identifier.endpage2422en_US
dc.identifier.issn0028-4793
dc.identifier.issn1533-4406
dc.identifier.issue25en_US
dc.identifier.pmid26083206en_US
dc.identifier.scopus2-s2.0-84931403287en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage2409en_US
dc.identifier.urihttps://doi.org/10.1056/NEJMoa1413462
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12920
dc.identifier.volume372en_US
dc.identifier.wosWOS:000356354600007en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherMassachusetts Medical Socen_US
dc.relation.ispartofNew England Journal Of Medicineen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleInherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infectionsen_US
dc.typeArticleen_US

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