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

Karin R. Engelhardt, Sean McGhee, Sabine Winkler, Atfa Sassi, Cristina Woellner, Gabriela Lopez-Herrera, Andrew Chen, Hong Sook Kim, Maria Garcia Lloret, Ilka Schulze, Stephan Ehl, Jens Thiel, Dietmar Pfeifer, Hendrik Veelken, Tim Niehues, Kathrin Siepermann, Sebastian Weinspach, Ismail Reisli, Sevgi Keles, Ferah Genel & 18 others Necil Kutuculer, Yildiz Camcioǧlu, Ayper Somer, Elif Karakoc-Aydiner, Isil Barlan, Andrew Gennery, Ayse Metin, Aydan Degerliyurt, Maria C. Pietrogrande, Mehdi Yeganeh, Zeina Baz, Salem Al-Tamemi, Christoph Klein, Jennifer M. Puck, Steven M. Holland, Edward R B McCabe, Bodo Grimbacher, Talal A. Chatila

Research output: Contribution to journalArticle

304 Citations (Scopus)

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. 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.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Volume124
Issue number6
DOIs
Publication statusPublished - Dec 2009

Fingerprint

Job Syndrome
Cytokinesis
Sequence Deletion
Point Mutation
Mutation
T-Lymphocytes
Th17 Cells
Virus Diseases
Atopic Dermatitis
Actin Cytoskeleton
Eosinophils
Haplotypes
Immunoglobulin E
Genes
Single Nucleotide Polymorphism
Cell Differentiation
Exons
Homeostasis
Complementary DNA

Keywords

  • Autosomal recessive hyper-IgE syndrome
  • copy number variations
  • DOCK8
  • eosinophils
  • genomic deletions
  • human gene mutation
  • IgE regulation
  • molluscum contagiosum
  • primary immunodeficiency
  • recurrent infection
  • T cells
  • T17 cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. / Engelhardt, 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; Camcioǧlu, 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.

In: Journal of Allergy and Clinical Immunology, Vol. 124, No. 6, 12.2009.

Research output: Contribution to journalArticle

Engelhardt, KR, McGhee, S, Winkler, S, Sassi, A, Woellner, C, Lopez-Herrera, G, Chen, A, Kim, HS, Lloret, MG, Schulze, I, Ehl, S, Thiel, J, Pfeifer, D, Veelken, H, Niehues, T, Siepermann, K, Weinspach, S, Reisli, I, Keles, S, Genel, F, Kutuculer, N, Camcioǧlu, Y, Somer, A, Karakoc-Aydiner, E, Barlan, I, Gennery, A, Metin, A, Degerliyurt, A, Pietrogrande, MC, Yeganeh, M, Baz, Z, Al-Tamemi, S, Klein, C, Puck, JM, Holland, SM, McCabe, ERB, Grimbacher, B & Chatila, TA 2009, 'Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome', Journal of Allergy and Clinical Immunology, vol. 124, no. 6. https://doi.org/10.1016/j.jaci.2009.10.038
Engelhardt, 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 ; Camcioǧlu, 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. / Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. In: Journal of Allergy and Clinical Immunology. 2009 ; Vol. 124, No. 6.
@article{0337e6c190624b3d8b044cbdb97a0f1f,
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. 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.",
keywords = "Autosomal recessive hyper-IgE syndrome, copy number variations, DOCK8, eosinophils, genomic deletions, human gene mutation, IgE regulation, molluscum contagiosum, primary immunodeficiency, recurrent infection, T cells, T17 cells",
author = "Engelhardt, {Karin R.} and Sean McGhee and Sabine Winkler and Atfa Sassi and Cristina Woellner and Gabriela Lopez-Herrera and Andrew Chen and Kim, {Hong Sook} and Lloret, {Maria Garcia} and Ilka Schulze and Stephan Ehl and Jens Thiel and Dietmar Pfeifer and Hendrik Veelken and Tim Niehues and Kathrin Siepermann and Sebastian Weinspach and Ismail Reisli and Sevgi Keles and Ferah Genel and Necil Kutuculer and Yildiz Camcioǧlu and Ayper Somer and Elif Karakoc-Aydiner and Isil Barlan and Andrew Gennery and Ayse Metin and Aydan Degerliyurt and Pietrogrande, {Maria C.} and Mehdi Yeganeh and Zeina Baz and Salem Al-Tamemi and Christoph Klein and Puck, {Jennifer M.} and Holland, {Steven M.} and McCabe, {Edward R B} and Bodo Grimbacher and Chatila, {Talal A.}",
year = "2009",
month = "12",
doi = "10.1016/j.jaci.2009.10.038",
language = "English",
volume = "124",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "6",

}

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.

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 - copy number variations

KW - DOCK8

KW - eosinophils

KW - genomic deletions

KW - human gene mutation

KW - IgE regulation

KW - molluscum contagiosum

KW - primary immunodeficiency

KW - recurrent infection

KW - T cells

KW - T17 cells

UR - http://www.scopus.com/inward/record.url?scp=71149115670&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=71149115670&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2009.10.038

DO - 10.1016/j.jaci.2009.10.038

M3 - Article

VL - 124

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 6

ER -