Novel Loss of Function (G15D) Mutation on RAC2 in a Family with Combined Immunodeficiency and Increased Levels of Immunoglobulin G, A, and E

Ras-related C3 botulinum toxin substrate 2 (RAC2) is a small guanine nucleotide binding molecule that is exclusively expressed in hematopoietic cell lineages as a switcher. Based on in vivo and/or in vitro model experiments, RAC2 plays important roles in different cells through proliferation, secret...

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Published in:Journal of clinical immunology 2023-04, Vol.43 (3), p.604-614
Main Authors: Duan, Xiaojun, Shen, Fang, Deng, Yafei, Zhang, Jin, Fang, Fan, Luo, Zhenqing, Chen, Yanping, Yang, Yongjia
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Autoimmune diseases
Biomedical and Life Sciences
Biomedicine
Botulinum toxin
Bronchiectasis
Cell proliferation
Common variable immunodeficiency
Hematopoietic stem cells
Human papillomavirus
Humans
Immune system
Immunoglobulin A
Immunoglobulin E
Immunoglobulin G
Immunoglobulin M
Immunoglobulins
Immunology
Infectious Diseases
Internal Medicine
Leukocytes (granulocytic)
Leukocytes (neutrophilic)
Lymphocytes
Medical Microbiology
Membrane potential
Mitochondria
Mutation
Original Article
Phagocytosis
Primary immunodeficiencies
Primary Immunodeficiency Diseases
RAC2 GTP-Binding Protein
Rac2 protein
Recurrent infection
Serum levels
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Summary:Ras-related C3 botulinum toxin substrate 2 (RAC2) is a small guanine nucleotide binding molecule that is exclusively expressed in hematopoietic cell lineages as a switcher. Based on in vivo and/or in vitro model experiments, RAC2 plays important roles in different cells through proliferation, secretion, and phagocytosis. It also performs a suppressing function in immunoglobulin (Ig) switching in Rac2 -/- animals or cells. Several RAC2 natural mutations have been described in patients with primary immunodeficiency. RAC2 mutations can be classified into loss-of-function inactivating (LoF-I) and gain-of-function activating mutations according to their functional effects. Only two LoF-I mutations on RAC2 have been reported, including a dominant D57N mutation in several cases that exhibit granulocyte function defects and a recessive D56X mutation in cases with common variable immunodeficiency. Regardless of the type of mutation, most of the reported RAC2 mutant cases have shown reduced IgG, IgA, and IgM levels. Herein, we report on a family with three members that suffer from persistent HPV infection, recurrent respiratory infections, bronchiectasis, and autoimmune disease. The immunologic profile suggests that the family was affected by combined immunodeficiency (CID) with increased serum levels of IgG, IgA, and IgE. Exome sequencing identified a de novo RAC2 mutation (c.44G > A/p.G15D) that was co-segregated with the disease in the family. Gene functional experiments identified that such mutation results in reduced guanosine triphosphate binding activity and RAC2 protein expression. In patients’ lymphocytes, impaired aggregation and proliferation effects, decreased mitochondrial membrane potential, and increased levels of cell apoptosis were observed, although no functional abnormalities were detected in neutrophils. To our knowledge, this study was the first to identify a LoF-I mutation of RAC2 affecting lymphocyte function that consequently led to CID and increased levels of serum IgG, IgE, and IgA. This study presents a novel subtype of RAC2 -related immune disorder.
ISSN:0271-9142
1573-2592
DOI:10.1007/s10875-022-01411-5