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

Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, UK.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 12/2009; 124(6):1289-302.e4. DOI: 10.1016/j.jaci.2009.10.038
Source: PubMed


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.

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Available from: Karin R Engelhardt
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    • "Subsequently, in 2009, mutations in the dedicator of cytokinesis-8 gene (DOCK8) were found to account for the majority of patients with AR-HIES [75,76]. Both homozygous and compound heterozygous mutations were reported and large deletions were frequent; and most of the individuals with DOCK8 mutations had absent or reduced levels of protein. "
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    • "Besides Bcl6, deficiency in other GC-related molecules results in higher production of IgE. Deficiency of dedicator of cytokinesis 8 (Dock8) caused unstable germinal centers in mice (Randall et al., 2009) and hyper-IgE syndrome (HIES) in humans (Engelhardt et al., 2009; Zhang et al., 2009). IL-21 is a critical cytokine produced by T FH cells; similarly to Bcl6 and Dock8, IL-21R-deficient mice have higher IgE and lower IgG1 level (Ozaki et al., 2002). "
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    • "Most patients affected by this disease are deficient in dedicator of cytokinesis 8 (DOCK8), leading to impaired T-cell activation and maintenance of memory. As in autosomal-dominant HIES, these patients have elevated IgE levels, eczema, recurrent bacterial infections and CMC [45,46]. The unique disease manifestations include susceptibility to recurrent viral infections (most commonly herpes viruses, molluscum contagiosum virus and human papillomaviruses), asthma, severe food allergies, malignancy at young age and unusual auto-immune diseases. "
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