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Lookup NU author(s): Dr Karin Engelhardt, Professor Andrew GenneryORCiD
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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 Th17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE. © 2009 American Academy of Allergy, Asthma & Immunology.
Author(s): Engelhardt K, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herrera G, Chen A, Kim H, Lloret M, Schulze I, Ehl S, Thiel J, Pfeifer D, Veelken H, Niehues T, Siepermann K, Weinspach S, Reisli I, Keles S, Genel F, Kutuculer N, Camcioǧlu Y, Somer A, Karakoc-Aydiner E, Barlan I, Gennery A, Metin A, Degerliyurt A, Pietrogrande M, Yeganeh M, Baz Z, Al-Tamemi S, Klein C, Puck J, Holland S, McCabe E, Grimbacher B, Chatila T
Publication type: Article
Publication status: Published
Journal: Journal of Allergy and Clinical Immunology
Year: 2009
Volume: 124
Issue: 6
Pages: 1289-1302.e4
Date deposited: 12/06/2014
ISSN (print): 0091-6749
ISSN (electronic): 1085-8725
Publisher: Mosby, Inc.
URL: http://dx.doi.org/10.1016/j.jaci.2009.10.038
DOI: 10.1016/j.jaci.2009.10.038
PubMed id: 20004785
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