%0 Journal Article %T Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome %+ University College of London [London] (UCL) %+ David Geffen School of Medicine [Los Angeles] %+ Laboratoire d'Immunopathologie, Vaccinologie et Génétique Moléculaire (LVGM) %+ Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany %+ Medical Department I %+ Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf] %+ Selcuk University %+ Behcet Uz State Hospital Division of Pediatric Immunology, Izmir %+ Department of Pediatrics %+ the Division of Pediatric Allergy-Immunology and Infectious Diseases %+ the Division of Infectious Diseases and Immunology %+ the Division of Pediatric Allergy and Immunology %+ Newcastle University [Newcastle] %+ the Pediatric Immunology Unit %+ the Department of Maternal and Pediatric Sciences %+ Helios Klinikum Krefeld - Helios Klinikum Krefeld %+ the Department of Pediatrics %+ the Department of Pediatrics %+ the Department of Pediatric Hematology/Oncology %+ University of California [San Francisco] (UC San Francisco) %+ the Laboratory of Clinical Infectious Diseases %+ the Departments of Pediatrics, Human Genetics, and Bioengineering, and the Center for Society and Genetics %+ Tehran University of Medical Sciences %A Engelhardt, Karin R. %A Mcghee, Sean %A Winkler, Sabine %A Sassi, Atfa %A Woellner, Cristina %A Lopez-Herrera, Gabriela %A Chen, Andrew %A Kim, Hong Sook %A Lloret, Maria Garcia %A Schulze, Ilka %A Ehl, Stephan %A Thiel, Jens %A Pfeifer, Dietmar %A Veelken, Hendrik %A Weinspach, Sebastian %A Reisli, Ismail %A Keles, Sevgi %A Genel, Ferah %A Kutuculer, Necil %A Camcioglu, Yildiz %A Somer, Ayper %A Karakoc-Aydiner, Elif %A Barlan, Isil %A Gennery, Andrew %A Metin, Ayse %A Degerliyurt, Aydan %A Pietrogrande, Maria C. %A Siepermann, Kathrin %A Baz, Zeina %A Al-Tamemi, Salem %A Klein, Christoph %A Puck, Jennifer M. %A Holland, Steven M. %A Niehues, Tim %A Mccabe, Edward R. B. %A Grimbacher, Bodo %A Yeganeh, Mehdi %A Chatila, Talal A. %< avec comité de lecture %@ 0091-6749 %J Journal of Allergy and Clinical Immunology %I Elsevier %V 124 %N 6 %P 1289-1302 %8 2009-12 %D 2009 %R 10.1016/j.jaci.2009.10.038 %K Autosomal recessive hyper-IgE syndrome %K human gene mutation %K DOCK8 %K primary immunodeficiency %K molluscum contagiosum %K recurrent infection %K T cells %K T(H)17 cells %K eosinophils %K IgE regulation %K copy number variations %K genomic deletions %Z Life Sciences [q-bio]Journal articles %X 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 wautosomal-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 T(H)17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE. (J Allergy Clin Immunol 2009;124:1289-302.) %G English %L pasteur-01375326 %U https://riip.hal.science/pasteur-01375326 %~ RIIP %~ RIIP_TUNIS