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Clin Immunol. 2019 Aug;205:1-5. doi: 10.1016/j.clim.2019.05.003. Epub 2019 May 7.

Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections.

Author information

1
Research department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk region, Belarus. Electronic address: sharapovasv@gmail.com.
2
Department of Hematology and Regenerative Medicine, Karolinska Institutet, Huddinge, Sweden; Biomedicum Stem Cell Center, University of Helsinki, Finland; Center for Molecular Medicine Norway, University of Oslo, Norway.
3
Research department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk region, Belarus.
4
West-Ukrainian Specialized Children's Medical Center, Lviv, Ukraine.
5
Molecular Defenses Section, Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, Bethesda, USA.
6
Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, USA.
7
Rivne Regional Children's Hospital, Rivne, Ukraine.
8
Department of Pediatric Infectious Diseases and Pediatric Immunology, P.L. Shupyk National Medical Academy for Postgraduate Education, Kiev, Ukraine.
9
Pediatric Bone Marrow Transplantation Unit, Medical Park Antalya Hospital, Antalya, Turkey.
10
Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, Bethesda, USA.

Abstract

Here we describe a 10-year-old girl with combined immunodeficiency presenting as recurring chest infections, lung disease and herpetic skin infections. The patient experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86. Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels. Whole exome sequencing (WES) identified a novel heterozygous mutation in RAC2(c.275A > C, p.N92 T). Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP. Cell lines transfected with RAC2 [N92 T] displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA. Our findings broaden the clinical picture of RAC2 dysfunction, showing that some individuals can present with a combined immunodeficiency later in childhood rather than a congenital neutrophil disease.

KEYWORDS:

Dominant activating RAC2 mutation; Infantile-onset humoral immunodeficiency; Viral infections

PMID:
31071452
DOI:
10.1016/j.clim.2019.05.003

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