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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 JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 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., Genel, F., Kutuculer, N., Camcioglu, Y., Somer, A., Karakoc-Aydiner, E., Barlan, I., Gennery, A., Metin, A., Degerliyurt, A., Pietrogrande, M. C., Yeganeh, M., Baz, Z., Al-Tamemi, S., Klein, C., Puck, J. M., Holland, S. M., McCabe, E. R., Grimbacher, B., Chatila, T. A. 2009; 124 (6): 1289-1302

Abstract

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.We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome.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.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.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.

View details for DOI 10.1016/j.jaci.2009.10.038

View details for Web of Science ID 000273071500022

View details for PubMedID 20004785