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

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 GenelNecil Kutuculer, Yildiz Camcioǧlu, 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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319 Citations (Scopus)

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 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.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Volume124
Issue number6
DOIs
Publication statusPublished - Dec 2009

Keywords

  • Autosomal recessive hyper-IgE syndrome
  • copy number variations
  • DOCK8
  • eosinophils
  • genomic deletions
  • human gene mutation
  • IgE regulation
  • molluscum contagiosum
  • primary immunodeficiency
  • recurrent infection
  • T cells
  • T17 cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Engelhardt, K. R., McGhee, S., Winkler, S., Sassi, A., Woellner, C., Lopez-Herrera, G., Chen, A., Kim, H. S., Lloret, M. G., Schulze, I., Ehl, S., Thiel, J., Pfeifer, D., Veelken, H., Niehues, T., Siepermann, K., Weinspach, S., Reisli, I., Keles, S., ... Chatila, T. A. (2009). 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, 124(6). https://doi.org/10.1016/j.jaci.2009.10.038