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Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome

Karin R. Engelhardt 1 Sean Mcghee 2 Sabine Winkler 1 Atfa Sassi 3 Cristina Woellner 1 Gabriela Lopez-Herrera 1 Andrew Chen 2 Hong Sook Kim 2 Maria Garcia Lloret 2 Ilka Schulze 4 Stephan Ehl 4 Jens Thiel 4 Dietmar Pfeifer 5 Hendrik Veelken 5 Sebastian Weinspach 6 Ismail Reisli 7 Sevgi Keles 7 Ferah Genel 8 Necil Kutuculer 9 Yildiz Camcioglu 10 Ayper Somer 11 Elif Karakoc-Aydiner 12 Isil Barlan 12 Andrew Gennery 13 Ayse Metin 14 Aydan Degerliyurt 14 Maria C. Pietrogrande 15 Kathrin Siepermann 16 Zeina Baz 17 Salem Al-Tamemi 18 Christoph Klein 19 Jennifer M. Puck 20 Steven M. Holland 21 Tim Niehues 16 Edward R. B. Mccabe 22 Bodo Grimbacher 4, 1 Mehdi Yeganeh 23 Talal A. Chatila 2
Abstract : 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.)
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Submitted on : Thursday, January 5, 2017 - 11:05:01 AM
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Karin R. Engelhardt, Sean Mcghee, Sabine Winkler, Atfa Sassi, Cristina Woellner, et al.. 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, Elsevier, 2009, 124 (6), pp.1289-1302. ⟨10.1016/j.jaci.2009.10.038⟩. ⟨pasteur-01375326⟩



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