Service interruption on Monday 11 July from 12:30 to 13:00: all the sites of the CCSD (HAL, EpiSciences, SciencesConf, AureHAL) will be inaccessible (network hardware connection).
Skip to Main content Skip to Navigation
Journal articles

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.)
Document type :
Journal articles
Complete list of metadata

https://hal-riip.archives-ouvertes.fr/pasteur-01375326
Contributor : Institut Pasteur Tunis Connect in order to contact the contributor
Submitted on : Thursday, January 5, 2017 - 11:05:01 AM
Last modification on : Monday, September 27, 2021 - 6:06:02 PM

Links full text

Identifiers

Collections

Citation

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⟩

Share

Metrics

Record views

165