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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome
Journal of Allergy and Clinical Immunology, Volume 124, No. 6, Year 2009
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Description
Background: The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60% to 70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining patients with hyper-IgE syndrome, the genetic etiology has not yet been identified. Objectives: We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome. Methods: We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with 12 patients from 7 additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal-recessive hyper-IgE syndrome. Results: Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p. In all 5 patients, the deleted interval involved dedicator of cytokinesis 8 (DOCK8), encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+T cells. Conclusion: Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T-cell activation and Th17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE. © 2009 American Academy of Allergy, Asthma & Immunology.
Authors & Co-Authors
Engelhardt, Karin R.
United Kingdom, London
University College London
McGhee, Sean Austin
United States, Los Angeles
David Geffen School of Medicine at Ucla
Johnson, Sabine
United Kingdom, London
University College London
Sassi, Atfa
Tunisia, Tunis
Institut Pasteur de Tunis
Woellner, Cristina
United Kingdom, London
University College London
López-Herrera, Gabriela
United Kingdom, London
University College London
Chen, Andrew
United States, Los Angeles
David Geffen School of Medicine at Ucla
Kim, Hong-sook
United States, Los Angeles
David Geffen School of Medicine at Ucla
Garcia-Lloret, Maria Ines
United States, Los Angeles
David Geffen School of Medicine at Ucla
Schulze, Ilka
Germany, Freiburg Im Breisgau
Universitätsklinikum Freiburg
Ehl, Stephan R.
Germany, Freiburg Im Breisgau
Universitätsklinikum Freiburg
Thiel, Jens Tobias
Germany, Freiburg Im Breisgau
Universitätsklinikum Freiburg
Pfeifer, Dietmar
Germany, Freiburg Im Breisgau
Universitätsklinikum Freiburg
Veelken, Hendrik
Germany, Freiburg Im Breisgau
Universitätsklinikum Freiburg
Niehues, Tim
Germany, Krefeld
Helios Klinikum Krefeld
Siepermann, Kathrin
Germany, Krefeld
Helios Klinikum Krefeld
Weinspach, Sebastian
Germany, Dusseldorf
Heinrich-heine-universität Düsseldorf
Reisli, Ïsmail
Turkey, Selçuklu
Selçuk Üniversitesi
Keleş, Sevgi
Turkey, Selçuklu
Selçuk Üniversitesi
Genel, Ferah
Turkey, Izmir
Behcet uz State Hospital Division of Pediatric Immunology
Kutuculer, Necil
Turkey, Izmir
Ege University Medical School
Camcioǧlu, Yildiz
Turkey, Istanbul
İstanbul Tıp Fakültesi
Somer, Ayper M.
Turkey, Istanbul
İstanbul Tıp Fakültesi
Karakoç-Aydiner, Elif
Turkey, Istanbul
Marmara Üniversitesi
Barlan, Işıl Berat
Turkey, Istanbul
Marmara Üniversitesi
Gennery, Andrew R.
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Metin, Ayşe
Turkey, Ankara
Sb Ankara Diskapi Children's Hospital
Deǧerliyurt, Aydan
Turkey, Ankara
Sb Ankara Diskapi Children's Hospital
Pietrogrande, Maria Cristina
Italy, Milan
Università Degli Studi Di Milano
Yeganeh, Mehdi
Iran, Tehran
Tehran University of Medical Sciences
Baz, Zeina
Lebanon, Beirut
Saint George Hospital University Medical Center
Al-Tamemi, Salem Hamdan
Oman, Muscat
Sultan Qaboos University
Klein, Christoph A.
Germany, Hannover
Hannover Biomedical Research School
Puck, Jennifer M.
United States, San Francisco
University of California, San Francisco
Holland, Steven M.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
McCabe, Edward R.B.
United States, Los Angeles
University of California, Los Angeles
Grimbacher, Bodo
United Kingdom, London
University College London
Chatila, T.
United States, Los Angeles
David Geffen School of Medicine at Ucla
Statistics
Citations: 479
Authors: 38
Affiliations: 21
Identifiers
Doi:
10.1016/j.jaci.2009.10.038
ISSN:
00916749
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Maternal And Child Health