| Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. | |
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MedLine Citation:
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PMID: 20004785 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 T(h)17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE. |
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Authors:
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Karin R Engelhardt; Sean McGhee; Sabine Winkler; Atfa Sassi; Cristina Woellner; Gabriela Lopez-Herrera; Andrew Chen; Hong Sook Kim; Maria Garcia Lloret; Ilka Schulze; Stephan Ehl; Jens Thiel; Dietmar Pfeifer; Hendrik Veelken; Tim Niehues; Kathrin Siepermann; Sebastian Weinspach; Ismail Reisli; Sevgi Keles; Ferah Genel; Necil Kutukculer; Necil Kutuculer; Yildiz Camcioğlu; Ayper Somer; Elif Karakoc-Aydiner; Isil Barlan; Andrew Gennery; Ayse Metin; Aydan Degerliyurt; Maria C Pietrogrande; Mehdi Yeganeh; Zeina Baz; Salem Al-Tamemi; Christoph Klein; Jennifer M Puck; Steven M Holland; Edward R B McCabe; Bodo Grimbacher; Talal A Chatila |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of allergy and clinical immunology Volume: 124 ISSN: 1097-6825 ISO Abbreviation: J. Allergy Clin. Immunol. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-12-16 Completed Date: 2010-01-12 Revised Date: 2011-03-03 |
Medline Journal Info:
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Nlm Unique ID: 1275002 Medline TA: J Allergy Clin Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 1289-302.e4 Citation Subset: AIM; IM |
Affiliation:
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Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, UK. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Child Child, Preschool Female Genes, Recessive Genome-Wide Association Study Guanine Nucleotide Exchange Factors / genetics* Haplotypes / genetics Homozygote Humans Job's Syndrome / genetics*, immunology, pathology Lymphocyte Activation / genetics, immunology Male Pedigree Point Mutation* Polymorphism, Single Nucleotide Sequence Deletion* T-Lymphocytes / immunology |
| Grant Support | |
ID/Acronym/Agency:
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1R21AI087627/AI/NIAID NIH HHS; 5R01AI065617/AI/NIAID NIH HHS; R01 AI065617-09/AI/NIAID NIH HHS; R01 AI065617-09S1/AI/NIAID NIH HHS; R21 AI087627-01/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DOCK8 protein, human; 0/Guanine Nucleotide Exchange Factors |
| Comments/Corrections | |
Erratum In:
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J Allergy Clin Immunol. 2010 Mar;125(3):743 Note: Kutuculer, Necil [corrected to Kutukculer, Necil] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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