Combined Immunodeficiency Associated with DOCK8 Mutations

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: 55.87). 09/2009; 361(21):2046-55. DOI: 10.1056/NEJMoa0905506
Source: PubMed


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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Available from: Amanda Favreau, Aug 25, 2014
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    • "In 2009, DOCK8 (Dedicator of cytokinesis 8) was independently determined to be the cause of significant immune deficiency both in humans and in mice [1] [2] [3]. These discoveries were made from positional data in the case of the human disease [1] [2], and from a mutagenesis screen in the case of the mouse disease [3]. "
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    ABSTRACT: First CanaryIslands(Spain) Inhabitants (“Guanches”) origin has been much debated. Lately, it has come popular the simplistic theory that they came from North Africa. In the present paper, we conclude that not only North Africans but also Iberian/Atlantic Europeans (and possibly others) must have been first Canarians. Debate whether North Africans or Iberians were the first “Guanches” is artificial since Iberian Peninsula-North African genes flow in ancient times was abundant and Iberians share a great part of genetic profile with North Africans. New genetic (HLA) and linguistic data shown in the present paper, is supported by diverse early anthropological and “Guanches” mummies characters which confirm existence of at least two “Guanches” types and a correct interpretation of R1b Y chromosome high frequency in Atlantic Europe (Ireland, British Isles, North Spain,Basque Coast and Portugal), and also, is present in Canary Islands (13.3%). Present paper HLA genes partial data and presence of abundant old Iberian language scripts (which show an easy translation proposal by using Basque) in Fuerteventura and also in Lanzarote and El Hierro Islands suggest that a present day dogma of a hypothetically North African single origin should be changed. Both Atlantic/Europeans and North Africans define origin of Canary Islands first inhabitants.Keywords: Basque, Canary Islands, El Hierro, Fuerteventura, genes, genetic markers, Guanche, HLA, Iberian, Language, Lanzarote, Latin Inscriptions, R1b, R1b1b, Rock scripts, Usko-Mediterranean, Y chromosome.
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    • ") Freeman and Holland (2009) Gain-of-function STAT1 mutations Liu et al. (2011) IL-17RA mutations Puel et al. (2011) IL-17F mutations ACT1 mutations Boisson et al. (2013) AIRE mutations (autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy [APECED] syndrome) Meloni et al. (2012) DOCK8 mutations (autosomal recessive hyper IgE syndrome [AR-HIES]) Zhang et al. (2009) CARD9 deficiency Glocker et al. (2009a) IRF8 mutations Hambleton et al. (2011) STK4 mutations Abdollahpour et al. (2012) Severe combined immunodeficiency (SCID) Mucocutaneous (including oral) viral susceptibility T cells/NKT cells/NK cells (often additional cell types involved) SCID WAS/WASP mutations (Wiskott-Aldrich syndrome) Buckley (2004) Binder et al. (2006) DOCK8 mutations (AR-HIES) Zhang et al. (2009) IKBKG/NEMO mutations (ectodermal dysplasia) Doffinger et al. (2001) CORO1A mutations: herpes simplex virus type 1 (HSV-1) and human papillomavirus (HPV) Stray-Pedersen et al. (2014) MHCII deficiency: HPV Guirat-Dhouib et al. (2012) "
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    ABSTRACT: In recent years, the study of genetic defects arising from inborn errors in immunity has resulted in the discovery of new genes involved in the function of the immune system and in the elucidation of the roles of known genes whose importance was previously unappreciated. With the recent explosion in the field of genomics and the increasing number of genetic defects identified, the study of naturally occurring mutations has become a powerful tool for gaining mechanistic insight into the functions of the human immune system. In this concise perspective, we discuss emerging evidence that inborn errors in immunity constitute real-life models that are indispensable both for the in-depth understanding of human biology and for obtaining critical insights into common diseases, such as those affecting oral health. In the field of oral mucosal immunity, through the study of patients with select gene disruptions, the interleukin-17 (IL-17) pathway has emerged as a critical element in oral immune surveillance and susceptibility to inflammatory disease, with disruptions in the IL-17 axis now strongly linked to mucosal fungal susceptibility, whereas overactivation of the same pathways is linked to inflammatory periodontitis. © International & American Associations for Dental Research 2015.
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    • "By definition, CVID does not have hypergammaglobulinemia, but other immunodeficiencies that have been described with elevated immunoglobulins can have autoimmune cytopenias. One example is DOCK8 deficiency (Zhang et al. 2009). "

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