TY - JOUR
T1 - Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome
AU - Engelhardt, Karin R.
AU - McGhee, Sean
AU - Winkler, Sabine
AU - Sassi, Atfa
AU - Woellner, Cristina
AU - Lopez-Herrera, Gabriela
AU - Chen, Andrew
AU - Kim, Hong Sook
AU - Lloret, Maria Garcia
AU - Schulze, Ilka
AU - Ehl, Stephan
AU - Thiel, Jens
AU - Pfeifer, Dietmar
AU - Veelken, Hendrik
AU - Niehues, Tim
AU - Siepermann, Kathrin
AU - Weinspach, Sebastian
AU - Reisli, Ismail
AU - Keles, Sevgi
AU - Genel, Ferah
AU - Kutuculer, Necil
AU - Camcioǧlu, Yildiz
AU - Somer, Ayper
AU - Karakoc-Aydiner, Elif
AU - Barlan, Isil
AU - Gennery, Andrew
AU - Metin, Ayse
AU - Degerliyurt, Aydan
AU - Pietrogrande, Maria C.
AU - Yeganeh, Mehdi
AU - Baz, Zeina
AU - Al-Tamemi, Salem
AU - Klein, Christoph
AU - Puck, Jennifer M.
AU - Holland, Steven M.
AU - McCabe, Edward R.B.
AU - Grimbacher, Bodo
AU - Chatila, Talal A.
N1 - Funding Information:
Supported by National Institutes of Health grants 5R01AI065617 and 1R21AI087627 to T.C. and by the EU Marie-Curie grant MEXT-CT-2006-042316 and the European Community's 7th Framework Programme FP7/2007-2013 grant EURO-PADnet HEALTH-F2-2008-201549 to B.G.
Funding Information:
Disclosure of potential conflict of interest: K. R. Engelhardt, S. Winkler, and G. Lopez-Herrera are employed on a research grant from the European Union (EU Marie-Curie grant). S. McGhee is a board member of Madison's Foundation. E. R. B. McCabe has received research support from the National Institutes of Health/National Human Genome Research Institute. B. Grimbacher (EU Marie-Curie grant) has received research support from the European Union and the Primary Immunodeficiency Association. The rest of the authors have declared that they have no conflict of interest.
PY - 2009/12
Y1 - 2009/12
N2 - 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.
AB - 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.
KW - Autosomal recessive hyper-IgE syndrome
KW - DOCK8
KW - IgE regulation
KW - T cells
KW - T17 cells
KW - copy number variations
KW - eosinophils
KW - genomic deletions
KW - human gene mutation
KW - molluscum contagiosum
KW - primary immunodeficiency
KW - recurrent infection
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U2 - 10.1016/j.jaci.2009.10.038
DO - 10.1016/j.jaci.2009.10.038
M3 - Article
C2 - 20004785
AN - SCOPUS:71149115670
SN - 0091-6749
VL - 124
SP - 1289-1302.e4
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 6
ER -