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

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dc.contributor.authorEngelhardt, Karin R.
dc.contributor.authorMcGhee, Sean
dc.contributor.authorWinkler, Sabine
dc.contributor.authorSassi, Atfa
dc.contributor.authorWoellner, Cristina
dc.contributor.authorLopez-Herrera, Gabriela
dc.contributor.authorChen, Andrew
dc.date.accessioned2020-03-26T17:39:06Z
dc.date.available2020-03-26T17:39:06Z
dc.date.issued2009
dc.departmentSelçuk Üniversitesien_US
dc.description.abstractBackground: 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 wautosomal-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. (J Allergy Clin Immunol 2009;124:1289-302.)en_US
dc.description.sponsorshipNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5R01AI065617, IR21AI087627]; EUEuropean Union (EU) [MEXT-CT-2006-042316, FP7/2007-2013, HEALTH-F2-2008-201549]en_US
dc.description.sponsorshipSupported by National Institutes of Health grants 5R01AI065617 and IR21AI087627 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.en_US
dc.identifier.doi10.1016/j.jaci.2009.10.038en_US
dc.identifier.endpage1302en_US
dc.identifier.issn0091-6749en_US
dc.identifier.issn1097-6825en_US
dc.identifier.issue6en_US
dc.identifier.pmid20004785en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1289en_US
dc.identifier.urihttps://dx.doi.org/10.1016/j.jaci.2009.10.038
dc.identifier.urihttps://hdl.handle.net/20.500.12395/23647
dc.identifier.volume124en_US
dc.identifier.wosWOS:000273071500022en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherMOSBY-ELSEVIERen_US
dc.relation.ispartofJOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGYen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.selcuk20240510_oaigen_US
dc.subjectAutosomal recessive hyper-IgE syndromeen_US
dc.subjecthuman gene mutationen_US
dc.subjectDOCK8en_US
dc.subjectprimary immunodeficiencyen_US
dc.subjectmolluscum contagiosumen_US
dc.subjectrecurrent infectionen_US
dc.subjectT cellsen_US
dc.subjectT(H)17 cellsen_US
dc.subjecteosinophilsen_US
dc.subjectIgE regulationen_US
dc.subjectcopy number variationsen_US
dc.subjectgenomic deletionsen_US
dc.titleLarge deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndromeen_US
dc.typeArticleen_US

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