Department of Pediatrics, Division of Genetics
B-Lymphocytes; Child, Preschool; Fatal Outcome; Female; Genes, Recessive; Genetic Diseases, Inborn; Guanine Nucleotide Exchange Factors; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Infant; Killer Cells, Natural; Male; *Mutation; Pedigree; T-Lymphocytes; rac1 GTP-Binding Protein
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics | Immune System Diseases | Immunity | Immunology of Infectious Disease | Medical Genetics | Molecular Genetics
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-alpha 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. (Supported by the National Institutes of Health and others.).
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DOI of Published Version
Dobbs K, Domínguez Conde C, Zhang SY, 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 JL, Boztuğ K, Notarangelo LD. Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections. N Engl J Med. 2015 Jun 18;372(25):2409-22. doi:10.1056/NEJMoa1413462. PubMed PMID: 26083206; PubMed Central PMCID: PMC4480434. Link to article on publisher's site
The New England journal of medicine
Zhang S, Comeau A, Casanova J, Boztug K, Notarangelo LD. (2015). Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections. Open Access Articles. https://doi.org/10.1056/NEJMoa1413462. Retrieved from https://escholarship.umassmed.edu/oapubs/2708
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