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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.authorAYDINER, ELİF
dc.contributor.authorsEngelhardt, Karin R.; McGhee, Sean; Winkler, Sabine; Sassi, Atfa; Woellner, Cristina; Lopez-Herrera, Gabriela; Chen, Andrew; Kim, Hong Sook; Lloret, Maria Garcia; Schulze, Ilka; Ehl, Stephan; Thiel, Jens; Pfeifer, Dietmar; Veelken, Hendrik; Niehues, Tim; Siepermann, Kathrin; Weinspach, Sebastian; Reisli, Ismail; Keles, Sevgi; Genel, Ferah; Kutuculer, Necil; Camcioglu, Yildiz; Somer, Ayper; Karakoc-Aydiner, Elif; Barlan, Isil; Gennery, Andrew; Metin, Ayse; Degerliyurt, Aydan; Pietrogrande, Maria C.; Yeganeh, Mehdi; Baz, Zeina; Al-Tamemi, Salem; Klein, Christoph; Puck, Jennifer M.; Holland, Steven M.; McCabe, Edward R. B.; Grimbacher, Bodo; Chatila, Talal A.
dc.date.accessioned2022-03-14T09:32:06Z
dc.date.available2022-03-14T09:32:06Z
dc.date.issued2009-12
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.)
dc.identifier.doi10.1016/j.jaci.2009.10.038
dc.identifier.eissn1097-6825
dc.identifier.issn0091-6749
dc.identifier.pubmed20004785
dc.identifier.urihttps://hdl.handle.net/11424/243236
dc.identifier.wosWOS:000273071500022
dc.language.isoeng
dc.publisherMOSBY-ELSEVIER
dc.relation.ispartofJOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectAutosomal recessive hyper-IgE syndrome
dc.subjecthuman gene mutation
dc.subjectDOCK8
dc.subjectprimary immunodeficiency
dc.subjectmolluscum contagiosum
dc.subjectrecurrent infection
dc.subjectT cells
dc.subjectT(H)17 cells
dc.subjecteosinophils
dc.subjectIgE regulation
dc.subjectcopy number variations
dc.subjectgenomic deletions
dc.subjectIDENTIFICATION
dc.subjectREARRANGEMENTS
dc.subjectGENOME
dc.titleLarge deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome
dc.typearticle
dspace.entity.typePublication
local.avesis.id32b79e61-6539-4f4e-87bf-79fff615eaac
local.import.packageSS16
local.indexed.atWOS
local.indexed.atSCOPUS
local.journal.numberofpages14
oaire.citation.endPage1302
oaire.citation.issue6
oaire.citation.startPage1289
oaire.citation.titleJOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
oaire.citation.volume124
relation.isAuthorOfPublication787c2629-584b-4b3e-9850-bf85838f2973
relation.isAuthorOfPublication.latestForDiscovery787c2629-584b-4b3e-9850-bf85838f2973

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