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.

Download full-text


Available from: Karin R Engelhardt,
89 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The hyper-IgE syndromes (HIES; originally named Job's syndrome) are a collection of primary immunodeficiency syndromes resulting in elevated serum IgE levels and typified by recurrent staphylococcal skin abscesses, eczema and pulmonary infections. The disorder has autosomal dominant and recessive forms. Autosomal dominant HIES has been shown to be mainly due to STAT3 mutations and additionally results in connective tissue, skeletal, vascular and dental abnormalities. Autosomal recessive HIES has been shown to be mainly due to mutations in DOCK8; these patients are more prone to viral skin infections instead. This review article discusses the common clinical features of the syndrome, the genetic mutations responsible and the pathogenesis of the disease, as well as treatments currently used.
    Arthritis research & therapy 11/2012; 14(6):228. DOI:10.1186/ar4069 · 3.75 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: IgE antibodies are involved in allergic reactions. High affinity IgE antibodies can cause anaphylaxis when cross-linked by minute amounts of antigen. The issue of how the IgE response is initiated and maintained is addressed in this review. A model has been proposed by which IgE(+) cells expressing antibodies that bind with high affinity to their antigens are generated through an IgG1 intermediate, which goes through affinity maturation in germinal centers (GC) before undergoing sequential switching to IgE. Mice deficient in IgG1 produce IgE at almost normal levels, but the IgE antibodies produced in IgG1-deficient mice lack the antigen-binding strength and the somatic mutations associated with affinity maturation. A GFP reporter strain, which expresses a modified IgE molecule, was recently developed and was utilized to challenge the sequential switching model. Several molecules that are highly expressed in GC can antagonize class switching to IgE in GC antagonize partially class switching to IgE; in addition, GC IgE(+) cells are gradually lost from GC as the immune response progresses, as shown with another recently developed, Venus-expressing IgE reporter mouse strain. In contrast, as a population, IgG1 cells thrive in the GC environment. Membrane IgE-expressing plasmablasts and plasma cells (PC) were recognized as a major component of the IgE response in secondary lymphoid organs. The swift development of IgE cells toward the PC fate, together with the affinity maturation of the IgE response via an IgG intermediate, represent the most salient features of the IgE immune responses, which make them distinct from IgG responses.
    Advances in Immunology 10/2012; 116:113-41. DOI:10.1016/B978-0-12-394300-2.00004-1 · 5.96 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: IL-17 and related cytokines are direct and indirect targets of selective immunosuppressive agents for the treatment of autoimmune diseases and other diseases of pathologic inflammation. Insights into the potential adverse effects of IL-17 blockade can be drawn from the experience of patients with deficiencies in the IL-17 pathway. A unifying theme of susceptibility to mucocutaneous candidiasis is seen in both mice and humans with a variety of genetic defects that converge on this pathway. Mucocutaneous candidiasis is a superficial infection of mucosal, nail or skin surfaces usually caused by the fungal pathogen Candida albicans. The morbidity of the disease includes significant pain, weight loss and secondary complications, including carcinoma and aneurysms. This review describes the known human diseases associated with chronic mucocutaneous candidiasis (CMC) as well as the known and proposed connections to IL-17 signaling. The human diseases include defects in IL-17 signaling due to autoantibodies (AIRE deficiency), receptor mutations (IL-17 receptor mutations) or mutations in the cytokine genes (IL17F and IL17A). Hyper-IgE syndrome is characterized by elevated serum IgE, dermatitis and recurrent infections, including CMC due to impaired generation of IL-17-producing Th17 cells. Mutations in STAT1, IL12B and IL12RB1 result in CMC secondary to decreased IL-17 production through different mechanisms. Dectin-1 defects and CARD9 defects result in susceptibility to C. albicans because of impaired host recognition of the pathogen and subsequent impaired generation of IL-17-producing T cells. Thus, recent discoveries of genetic predisposition to CMC have driven the recognition of the role of IL-17 in protection from mucosal fungal infection and should guide counseling and management of patients treated with pharmacologic IL-17 blockade.
    Arthritis research & therapy 07/2012; 14(4):217. DOI:10.1186/ar3893 · 3.75 Impact Factor
Show more