Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome.
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.
Engelhardt
Karin R
KR
Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, UK.
McGhee
Sean
S
Winkler
Sabine
S
Sassi
Atfa
A
Woellner
Cristina
C
Lopez-Herrera
Gabriela
G
Chen
Andrew
A
Kim
Hong Sook
HS
Lloret
Maria Garcia
MG
Schulze
Ilka
I
Ehl
Stephan
S
Thiel
Jens
J
Pfeifer
Dietmar
D
Veelken
Hendrik
H
Niehues
Tim
T
Siepermann
Kathrin
K
Weinspach
Sebastian
S
Reisli
Ismail
I
Keles
Sevgi
S
Genel
Ferah
F
Kutukculer
Necil
N
Kutuculer
Necil
N
Camcioğlu
Yildiz
Y
Somer
Ayper
A
Karakoc-Aydiner
Elif
E
Barlan
Isil
I
Gennery
Andrew
A
Metin
Ayse
A
Degerliyurt
Aydan
A
Pietrogrande
Maria C
MC
Yeganeh
Mehdi
M
Baz
Zeina
Z
Al-Tamemi
Salem
S
Klein
Christoph
C
Puck
Jennifer M
JM
Holland
Steven M
SM
McCabe
Edward R B
ER
Grimbacher
Bodo
B
Chatila
Talal A
TA
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
C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors