Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med

Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
New England Journal of Medicine (Impact Factor: 54.42). 09/2009; 361(21):2046-55. DOI: 10.1056/NEJMoa0905506
Source: PubMed

ABSTRACT Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown.
We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry.
Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma-leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes.
Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency.

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    • "Homozygous FREM1 gene frameshift and missense mutations were associated with bifid nose, anorectal and renal anomalies (BNAR [OMIM 608980]) (Alazami et al., 2009), and our patient presented three superior oral frenula and genital anomalies similar to BNAR patients. Also localized in the critical subtelomeric region of 9p (9p24) is the DOCK8 gene that has been associated to the autosomal recessive Hyper-IgE Recurrent Infection Syndrome, since DOCK8 mutations have been described in patients with recurrent infections , atopic dermatitis, and food and environmental allergies (Zhang et al., 2009). The loss of DOCK8 heterozygosity might be responsible for the recurrent infections observed in 9p deletion syndrome patients like ours. "
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    • "March 2012 | Volume 3 | Article 37 | 7 1999). Hence, primary immune deficiencies with defective quality of signal 1, such as Wiskott-Aldrich syndrome and DOCK8 immunodeficiency patients, share clinical characteristics (e.g., eczema, elevated IgE levels, cutaneous M. contagiosum or Papilloma and Herpes viral infections, and increased tumor incidence (Bosticardo et al., 2009; Zhang et al., 2009). Both Dock8 and WAS protein are important for T cell synapse formation (Dupre et al., 2002; Randall et al., 2011), and crucial for interactions between naive CD8 + T cells and DC (Pulecio et al., 2008; Randall et al., 2011). "
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    • "Besides Bcl6, deficiency in other GC-related molecules results in higher production of IgE. Deficiency of dedicator of cytokinesis 8 (Dock8) caused unstable germinal centers in mice (Randall et al., 2009) and hyper-IgE syndrome (HIES) in humans (Engelhardt et al., 2009; Zhang et al., 2009). IL-21 is a critical cytokine produced by T FH cells; similarly to Bcl6 and Dock8, IL-21R-deficient mice have higher IgE and lower IgG1 level (Ozaki et al., 2002). "
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