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J Clin Immunol. 2019 Mar 5. doi: 10.1007/s10875-019-00603-w. [Epub ahead of print]

Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction.

Author information

1
Laboratory for Inborn Errors of Immunity, Department of Immunology and Microbiology, KU Leuven, Leuven, EU, Belgium.
2
Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, EU, Belgium.
3
Department of Pediatrics, University Hospitals Leuven, Leuven, EU, Belgium.
4
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, USA.
5
Institute for Regenerative Medicine associated group, University of Zürich, Zürich, Switzerland.
6
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, EU, France.
7
Paris Descartes University, Imagine Institute, Paris, EU, France.
8
Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, México, Mexico.
9
Laboratory of Organ Systems, Department of Development and Regeneration, KU Leuven, Leuven, EU, Belgium.
10
Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, EU, Belgium.
11
Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, University Hospitals Leuven, KU Leuven, Leuven, EU, Belgium.
12
Center for Human Genetics, University Hospitals Leuven, Leuven, EU, Belgium.
13
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, EU, France.
14
INSERM UMR1163, University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, EU, France.
15
Division of Pediatric Hematology Oncology, Centre Hospitalier Chrétien, Montegnée, Liege, EU, Belgium.
16
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, 2010, Australia.
17
St. Vincent's Clinical School, Faculty of Medicine, University of NSW Sydney, Darlinghurst, New South Wales, 2010, Australia.
18
Howard Hughes Medical Institute, New York, NY, USA.
19
Immuno-Hémato-Rhumatologie Pédiatrique, Service de Pédiatrie, CHR Citadelle, Liège, EU, Belgium.
20
Centre for Applied Biotechnology and Molecular Medicine, University of Zürich, Zürich, Switzerland.
21
Zurich Centre for Integrative Human Physiology, Zürich, Switzerland.
22
Study Centre for Immunodeficiency, Necker Hospital for Sick Children, Paris, EU, France.
23
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA.
24
Laboratory for Inborn Errors of Immunity, Department of Immunology and Microbiology, KU Leuven, Leuven, EU, Belgium. isabelle.meyts@uzleuven.be.
25
Department of Pediatrics, University Hospitals Leuven, Leuven, EU, Belgium. isabelle.meyts@uzleuven.be.

Abstract

DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils.

KEYWORDS:

DOCK2; neutrophil dysfunction

PMID:
30838481
DOI:
10.1007/s10875-019-00603-w

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