Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation.
Actins
/ genetics
Botulinum Toxins
/ genetics
Caspase 3
/ genetics
Cytokines
/ metabolism
Gain of Function Mutation
Guanosine Triphosphate
/ metabolism
Humans
Immunoglobulin G
/ metabolism
Mutation
/ genetics
Primary Immunodeficiency Diseases
/ genetics
Reactive Oxygen Species
/ metabolism
Receptors, Antigen, T-Cell
/ genetics
rac GTP-Binding Proteins
/ genetics
Apoptosis,
Combined immunodeficiency,
Polarization
Ras-related C3 botulinum toxin substrate 2 (RAC2),
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
27
01
2022
accepted:
02
05
2022
pubmed:
22
5
2022
medline:
12
10
2022
entrez:
21
5
2022
Statut:
ppublish
Résumé
Ras-related C3 botulinum toxin substrate 2 (RAC2) is a GTPase exclusively expressed in hematopoietic cells that acts as a pivotal regulator of several aspects of cell behavior via various cellular processes. RAC2 undergoes a tightly regulated GTP-binding/GTP-hydrolysis cycle, enabling it to function as a molecular switch. Mutations in RAC2 have been identified in 18 patients with different forms of primary immunodeficiency, ranging from phagocyte defects caused by dominant negative mutations to common variable immunodeficiency resulting from autosomal recessive loss-of-function mutations, or severe combined immunodeficiency due to dominant activating gain-of-function mutations. Here, we describe an 11-year-old girl with combined immunodeficiency presenting with recurrent respiratory infections and bronchiectasis. Immunological investigations revealed low T-cell receptor excision circle/K-deleting recombination excision circles numbers, lymphopenia, and low serum immunoglobulin G. Targeted next-generation sequencing identified a novel heterozygous mutation in RAC2, c.86C > G (p.P29R), located in the highly conserved Switch I domain. The mutation resulted in enhanced reactive oxygen species production, elevated F-actin content, and increased RAC2 protein expression in neutrophils, as well as increased cytokine production and a dysregulated phenotype in T lymphocytes. Furthermore, the dominant activating RAC2 mutation led to accelerated apoptosis with augmented intracellular active caspase 3, impaired actin polarization in lymphocytes and neutrophils, and diminished RAC2 polarization in neutrophils. We present a novel RAC2 gain-of-function mutation with implications for immunodeficiency and linked to functional dysregulation, including abnormal apoptosis and cell polarization arising from altered RAC2 expression. Thus, our findings broaden the spectrum of known RAC2 mutations and their underlying mechanisms.
Identifiants
pubmed: 35596857
doi: 10.1007/s10875-022-01288-4
pii: 10.1007/s10875-022-01288-4
doi:
Substances chimiques
Actins
0
Cytokines
0
Immunoglobulin G
0
Reactive Oxygen Species
0
Receptors, Antigen, T-Cell
0
Guanosine Triphosphate
86-01-1
Caspase 3
EC 3.4.22.-
Botulinum Toxins
EC 3.4.24.69
rac GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1280-1292Subventions
Organisme : Chongqing Municipal Education Commission
ID : 2019–9-66
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008;9(9):690–701.
pubmed: 18719708
Mulloy JC, Cancelas JA, Filippi MD, et al. Rho GTPases in hematopoiesis and hemopathies. Blood. 2010;115(5):936–47.
pubmed: 19965643
pmcid: 2817638
Roberts AW, Kim C, Zhen L, et al. Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity. 1999;10(2):183–96.
pubmed: 10072071
Croker BA, Tarlinton DM, Cluse LA, et al. The Rac2 guanosine triphosphatase regulates B lymphocyte antigen receptor responses and chemotaxis and is required for establishment of B-1a and marginal zone B lymphocytes. J Immunol. 2002;168(7):3376–86.
pubmed: 11907095
Jansen M, Yang FC, Cancelas JA, et al. Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure. Stem Cells. 2005;23:335–46.
pubmed: 15749928
Arana E, Vehlow A, Harwood NE, et al. Activation of the small GTPase Rac2 via the B cell receptor regulates B cell adhesion and immunological-synapse formation. Immunity. 2008;28(1):88–99.
pubmed: 18191593
Savina A, Peres A, Cebrian I, et al. The small GTPase Rac2 controls phagosomal alkalinization and antigen crosspresentation selectively in CD8+ dendritic cells. Immunity. 2009;30(4):544–55.
pubmed: 19328020
Faroudi M, Hons M, Zachacz A, et al. Critical roles for Rac GTPases in T-cell migration to and within lymph nodes. Blood. 2010;116(25):5536–47.
pubmed: 20870900
pmcid: 3368586
Troeger A, Williams DA. Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders. Exp Cell Res. 2013;319(15):2375–83.
pubmed: 23850828
pmcid: 3997055
Janssen E, Geha RS. Primary immunodeficiencies caused by mutations in actin regulatory proteins. Immunol Rev. 2019;287(1):121–34.
pubmed: 30565251
Lougaris V, Baronio M, Gazzurelli L, et al. RAC2 and primary human immune deficiencies. J Leukoc Biol. 2020;108(2):687–96.
pubmed: 32542921
El Masri R, Delon J. RHO GTPases: from new partners to complex immune syndromes. Nat Rev Immunol. 2021;21(8):499–513.
pubmed: 33547421
Ambruso DR, Knall C, Abell AN, et al. Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A. 2000;97(9):4654–9.
pubmed: 10758162
pmcid: 18288
Williams DA, Tao W, Yang F, et al. Dominant negative mutation of the hematopoietic specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood. 2000;96(5):1646–54.
pubmed: 10961859
Gu Y, Jia B, Yang FC, et al. Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency. J Biol Chem. 2001;276(19):15929–38.
pubmed: 11278678
Routes JM, Grossman WJ, Verbsky J, et al. Statewide newborn screening for severe T-cell lymphopenia. JAMA. 2009;302(22):2465–70.
pubmed: 19996402
Accetta D, Syverson G, Bonacci B, et al. Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia. J Allergy Clin Immunol. 2011;127:535–8.
pubmed: 21167572
Alkhairy OK, Rezaei N, Graham RR, et al. RAC2 loss-of-function mutation in 2 siblings with characteristics of common variable immunodeficiency. J Allergy Clin Immunol. 2015;135(5):1380-4.e1-5.
pubmed: 25512081
Hodge RG, Ridley AJ. Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Biol. 2016;17(8):496–510.
pubmed: 27301673
Lougaris V, Chou J, Beano A, et al. A monoallelic activating mutation in RAC2 resulting in a combined immunodeficiency. J Allergy Clin Immunol. 2019;143(4):1649-1653.e3.
pubmed: 30654050
Hsu AP, Donkó A, Arrington ME, et al. Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood. 2019;133(18):1977–88.
pubmed: 30723080
pmcid: 6497516
Sharapova SO, Haapaniemi E, Sakovich IS, et al. Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections. Clin Immunol. 2019;205:1–5.
pubmed: 31071452
Smits BM, Lelieveld PHC, Ververs FA, et al. A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease. Clin Immunol. 2020;212: 108248.
pubmed: 31382036
Lagresle-Peyrou C, Olichon A, Sadek H, et al. A gain-of-function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency. Haematologica. 2021;106(2):404–11.
pubmed: 31919089
Stern H, Donkó A, Shapiro T, et al. A novel RAC2 variant presenting as severe combined immunodeficiency. J Clin Immunol. 2021;41(2):473–6.
pubmed: 33188496
Yang L, Xue X, Zeng T, et al. Novel biallelic TRNT1 mutations lead to atypical SIFD and multiple immune defects. Genes Dis. 2020;7(1):128–37.
pubmed: 32181284
pmcid: 7063413
Jenks SA, Cashman KS, Zumaquero E, et al. Distinct effector B cells induced by unregulated Toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity. 2018;49(4):725-739.e6.
pubmed: 30314758
pmcid: 6217820
Boyum A, Lovhaug D, Tresland L, Nordlie EM. Separation of leucocytes: improved cell purity by fine adjustments of gradient medium density and osmolality. Scand J Immunol. 1991;34(6):697–712.
pubmed: 1749920
Wekell P, Björnsdottir H, Björkman L, et al. Neutrophils from patients with SAPHO syndrome show no signs of aberrant NADPH oxidasedependent production of intracellular reactive oxygen species. Rheumatology (Oxford). 2016;55(8):1489–98.
Sottini A, Serana F, Bertoli D, et al. Simultaneous quantification of T-cell receptor excision circles (TRECs) and K-deleting recombination excision circles (KRECs) by real-time PCR. J Vis Exp. 2014;94:52184.
Bylund J, Björnsdottir H, Sundqvist M, et al. Measurement of respiratory burst products, released or retained, during activation of professional phagocytes. Methods Mol Biol. 2014;1124:321–38.
pubmed: 24504962
Paccani SR, Boncristiano M, Patrussi L, et al. Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects. Blood. 2005;106(2):626–34.
pubmed: 15817684
Honda F, Kano H, Kanegane H, et al. The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils. Nat Immunol. 2012;13(4):369–78.
pubmed: 22366891
Gabl M, Holdfeldt A, Sundqvist M, et al. FPR2 signaling without β-arrestin recruitment alters the functional repertoire of neutrophils. Biochem Pharmacol. 2017;145:114–22.
pubmed: 28855087
Mao H, Yang W, Latour S, et al. RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease. J Allergy Clin Immunol. 2018;142(2):595-604.e16.
pubmed: 29155103
Escobar D, Pons J, Clemente A, et al. Defective B cell response to TLR9 ligand (CpG-ODN), Streptococcus pneumoniae and Haemophilus influenzae extracts in common variable immunodeficiency patients. Cell Immunol. 2010;262(2):105–11.
pubmed: 20171611
Bunney TD, Opaleye O, Roe SM, et al. Structural insights into formation of an active signaling complex between Rac and phospholipase C Gamma 2. Mol Cell. 2009;34(2):223–33.
pubmed: 19394299
Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell. 2012;150(2):251–63.
pubmed: 22817889
pmcid: 3600117
Krauthammer M, Kong Y, Ha BH, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012;44(9):1006–14.
pubmed: 22842228
pmcid: 3432702
Kawazu M, Ueno T, Kontani K, et al. Transforming mutations of RAC guanosine triphosphatases in human cancers. Proc Natl Acad Sci U S A. 2013;110(8):3029–34.
pubmed: 23382236
pmcid: 3581941
Richards S, Aziz N, Bale S, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.
pubmed: 25741868
pmcid: 4544753
Filippi MD, Harris CE, Meller J, et al. Localization of Rac2 via the C terminus and aspartic acid 150 specifies superoxide generation, actin polarity and chemotaxis in neutrophils. Nat Immunol. 2004;5(7):744–51.
pubmed: 15170212
Lawson CD, Burridge K. The on-off relationship of Rho and Rac during integrin-mediated adhesion and cell migration. Small GTPases. 2014;5: e27958.
pubmed: 24607953
pmcid: 4114617
Lorès P, Morin L, Luna R, Gacon G. Enhanced apoptosis in the thymus of transgenic mice expressing constitutively activated forms of human Rac2GTPase. Oncogene. 1997;15(5):601–5.
pubmed: 9247314
Cancelas JA, Williams DA. Rho GTPases in hematopoietic stem cell functions. Curr Opin Hematol. 2009;16(4):249–54.
pubmed: 19417647
pmcid: 3908896
Guo F, Cancelas JA, Hildeman D, et al. Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development. Blood. 2008;112(5):1767–75.
pubmed: 18579797
pmcid: 2518885
Dumont C, Corsoni-Tadrzak A, Ruf S, et al. Rac GTPases play critical roles in early T-cell development. Blood. 2009;113(17):3990–8.
pubmed: 19088377
pmcid: 2673125
Amato C, Thomason PA, Davidson AJ, et al. WASP restricts active Rac to maintain cells’ front rear polarization. Curr Biol. 2019;29(24):4169-4182.e4.
pubmed: 31786060
pmcid: 6926487
Schlam D, Bagshaw RD, Freeman SA, et al. Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase activating. Nat Commun. 2015;6:8623.
pubmed: 26465210
Fujii M, Kawai K, Egami Y, Araki N. Dissecting the roles of Rac1 activation and deactivation in macropinocytosis using microscopic photo-manipulation. Sci Rep. 2013;3:2385.
pubmed: 23924974
pmcid: 3737501
Li B, Yu H, Zheng W, et al. Role of the guanosinetriphosphatase Rac2 in T helper 1 cell differentiation. Science. 2000;288(5474):2219–22.
pubmed: 10864872
Campa CC, Ciraolo E, Ghigo A, et al. Crossroads of PI3K and Rac pathways. Small GTPases. 2015;6(2):71–80.
pubmed: 25942647
pmcid: 4601376
Tabellini G, Baronio M, Patrizi O, et al. The RAC2-PI3K axis regulates human NK cell maturation and function. Clin Immunol. 2019;208: 108257.
pubmed: 31491520
Nunes-Santos CJ, Uzel G, Rosenzweig SD. PI3K pathway defects leading to immunodeficiency and immune dysregulation. J Allergy Clin Immunol. 2019;143(5):1676–87.
pubmed: 31060715