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SHR Neuro Cancer Cardio Lipid Metab Microb
Engelhardt, KR; McGhee, S; Winkler, S; Sassi, A; Woellner, C; Lopez-Herrera, G; Chen, A; Kim, HS; Lloret, MG; Schulze, I; Ehl, S; Thiel, J; Pfeifer, D; Veelken, H; Niehues, T; Siepermann, K; Weinspach, S; Reisli, I; Keles, S; Genel, F; Kutukculer, N; Kutuculer, N; Camcioğlu, Y; Somer, A; Karakoc-Aydiner, E; Barlan, I; Gennery, A; Metin, A; Degerliyurt, A; Pietrogrande, MC; Yeganeh, M; Baz, Z; Al-Tamemi, S; Klein, C; Puck, JM; Holland, SM; McCabe, ER; Grimbacher, B; Chatila, TA.
Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome.
J ALLERGY CLIN IMMUN. 2009; 124(6): 1289-302.e4.
Doi: 10.1016/j.jaci.2009.10.038
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- Co-authors Med Uni Graz
- Thiel Jens
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- 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 T(h)17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE.
- Find related publications in this database (using NLM MeSH Indexing)
- Child - administration & dosage
- Child, Preschool - administration & dosage
- Female - administration & dosage
- Genes, Recessive - administration & dosage
- Genome-Wide Association Study - administration & dosage
- Guanine Nucleotide Exchange Factors - genetics
- Haplotypes - genetics
- Homozygote - administration & dosage
- Humans - administration & dosage
- Job Syndrome - genetics, immunology, pathology
- Lymphocyte Activation - genetics, immunology
- Male - administration & dosage
- Pedigree - administration & dosage
- Point Mutation - administration & dosage
- Polymorphism, Single Nucleotide - administration & dosage
- Sequence Deletion - administration & dosage
- T-Lymphocytes - immunology
- Find related publications in this database (Keywords)
- Autosomal recessive hyper-IgE syndrome
- human gene mutation
- DOCK8
- primary immunodeficiency
- molluscum contagiosum
- recurrent infection
- T cells
- T(H)17 cells
- eosinophils
- IgE regulation
- copy number variations
- genomic deletions