title: Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, UK.
authors.forename: Karin R
authors.initials: KR
authors.lastname: Engelhardt
authors.forename: Sean
authors.initials: S
authors.lastname: McGhee
authors.forename: Sabine
authors.initials: S
authors.lastname: Winkler
authors.forename: Atfa
authors.initials: A
authors.lastname: Sassi
authors.forename: Cristina
authors.initials: C
authors.lastname: Woellner
authors.forename: Gabriela
authors.initials: G
authors.lastname: Lopez-Herrera
authors.forename: Andrew
authors.initials: A
authors.lastname: Chen
authors.forename: Hong Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Maria Garcia
authors.initials: MG
authors.lastname: Lloret
authors.forename: Ilka
authors.initials: I
authors.lastname: Schulze
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.forename: Jens
authors.initials: J
authors.lastname: Thiel
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Hendrik
authors.initials: H
authors.lastname: Veelken
authors.forename: Tim
authors.initials: T
authors.lastname: Niehues
authors.forename: Kathrin
authors.initials: K
authors.lastname: Siepermann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Weinspach
authors.forename: Ismail
authors.initials: I
authors.lastname: Reisli
authors.forename: Sevgi
authors.initials: S
authors.lastname: Keles
authors.forename: Ferah
authors.initials: F
authors.lastname: Genel
authors.forename: Necil
authors.initials: N
authors.lastname: Kutukculer
authors.forename: Necil
authors.initials: N
authors.lastname: Kutuculer
authors.forename: Yildiz
authors.initials: Y
authors.lastname: Camcioğlu
authors.forename: Ayper
authors.initials: A
authors.lastname: Somer
authors.forename: Elif
authors.initials: E
authors.lastname: Karakoc-Aydiner
authors.forename: Isil
authors.initials: I
authors.lastname: Barlan
authors.forename: Andrew
authors.initials: A
authors.lastname: Gennery
authors.forename: Ayse
authors.initials: A
authors.lastname: Metin
authors.forename: Aydan
authors.initials: A
authors.lastname: Degerliyurt
authors.forename: Maria C
authors.initials: MC
authors.lastname: Pietrogrande
authors.forename: Mehdi
authors.initials: M
authors.lastname: Yeganeh
authors.forename: Zeina
authors.initials: Z
authors.lastname: Baz
authors.forename: Salem
authors.initials: S
authors.lastname: Al-Tamemi
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Edward R B
authors.initials: ER
authors.lastname: McCabe
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007589:Job Syndrome / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors