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Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects
Open accessAbstract
Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67phox, activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Cell lines transfected with RAC2[E62K] displayed characteristics of active guanosine triphosphate (GTP)–bound RAC2 including enhanced superoxide production and increased membrane ruffling. Biochemical studies demonstrated that RAC2[E62K] retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2. Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients. This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates RAC2 from the related, ubiquitous RAC1.
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TL;DR
Three unrelated patients with de novo heterozygous RAC2 c.184G>A p.E62K had a dominant activating mutation causing T- and B-cell lymphopenia, myeloid dysfunction, recurrent infections, and cytoskeletal defects. Biochemical and mouse studies showed impaired GAP-mediated GTP hydrolysis, prolonged active RAC2, and Rac2+/E62K mice phenocopying patient lymphopenia, increased neutrophil F-actin, and excessive superoxide production.
Key findings
- All 3 patients had de novo heterozygous RAC2 c.184G>A p.E62K and T- and B-cell lymphopenia; patient 1 had recurrent pulmonary infections, pancytopenia, and bronchiectasis complicated by Aspergillus spp., Staphylococcus aureus, Mycobacterium abscessus, and Mycobacterium avium complex, while patient 2 had low TRECs (13/mL) and patient 3 had recurrent herpes stomatitis and otitis media with marked diminution in lymphocyte subsets.
- Patient neutrophils showed excessive fMLF-induced superoxide production, with cumulative O2− production 3- to 4-fold greater than healthy controls, plus impaired fMLF-directed chemotaxis, increased F-actin, and abnormal macropinocytosis with increased FITC-dextran uptake.
- RAC2[E62K]-transfected cells showed elevated basal ROS, increased PAK1-PBD-associated RAC2, increased pAKT, increased membrane ruffling, and large vesicles; biochemically, p50RhoGAP increased RAC2[WT] GTP hydrolysis sixfold but failed to accelerate RAC2[E62K] hydrolysis, and TIAM1-mediated GDP exchange was impaired.
- Rac2+/E62K mice had a >20-fold decrease in CD3+ T cells, decreased B cells and NK1.1+ cells (NK difference not statistically significant), lower splenic TCRαβ+ T cells with a larger CD8+ than CD4+ decrease, increased Mac1+ cells, and increased fMLF-induced O2− production and neutrophil F-actin.
Methods
- Clinical and immunologic evaluation of 3 patients with de novo RAC2 E62K, including whole-exome sequencing, targeted immunodeficiency gene panels, Sanger confirmation, and IRB-approved NIAID protocol participation.
- In vitro studies used patient neutrophils for F-actin staining, EZ-TAXIScan chemotaxis, FITC-dextran macropinocytosis, and cytochrome c superoxide assays; COS-7 or RAW264.7 cells were transfected with RAC2[WT] or RAC2[E62K] plus NADPH oxidase components for ROS, GST-PAK1-PBD binding, western blot, and confocal microscopy; recombinant RAC2 proteins were used for TIAM1 GDP exchange and p50RhoGAP GTP hydrolysis assays.
- Rac2+/E62K mice were generated by CRISPR/Cas9 in C57BL/6 embryos; peripheral blood, spleen, and thymus lymphocyte subsets were analyzed by flow cytometry, and bone marrow neutrophils were assayed for fMLF-induced superoxide and F-actin.
Limitations
- The paper does not include a formal limitations section; it notes that additional experiments such as synchronized intrathymic injections or thymic-section microscopy may help elucidate the mechanism of Rac2+/E62K lymphopenia, and that patients 2 and 3 had normal Boyden chamber chemotaxis before NIH referral, highlighting the importance of direct individual-cell tracking.
- Evident from the text: the human cohort is very small (3 patients), and the mouse model recapitulates major lymphoid and neutrophil defects but some differences, such as NK1.1+ cell reduction, did not reach statistical significance.
- Evident from the text: the precise mechanism by which RAC2[E62K] causes T- and B-cell lymphopenia is not fully defined, as thymic maturation appeared intact and the lymphopenia was not explained by bone marrow emigration into the thymus.
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In the paper
“Targeted in-house immunodeficiency gene panel at Lurie Children's Hospital identified de novo heterozygous RAC2 c.184G.A, p.E62K.”
§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > Study patients
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“Abnormal neutrophils were apparent in all 3 patients by light microscopy.”
§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > RAC2[E62K] patient neutrophils have aberrant macropinocytotic vesicles
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In the paper
“Antibodies to tetanus, varicella, and a few pneumococcal serotypes were adequate with poor response to Haemophilus influenzae type b.”
§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > Study patients
plainSingle case- Asserted: passes — The authors put it forward as true.
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“resulting in severe T-and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections.”
§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > Abstract
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“resulting in severe T-and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections.”
§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > Abstract
plainstates a causen = 3- Asserted: passes — The authors put it forward as true.
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In the citing paper
“The E62K mutation is a gain-of-function mutation localized in the G3/Switch II domain that was shown to be associated with a myeloid deficit, an altered neutrophil function, and lymphopenia (Hsu et al., 2019).”
From RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation (2024) · cites this paper as Hsu et al., 2019
In the citing paper
“The E62K mutation is a gain-of-function mutation localized in the G3/Switch II domain that was shown to be associated with a myeloid deficit, an altered neutrophil function, and lymphopenia (Hsu et al., 2019).”
From RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation (2024) · cites this paper as Hsu et al., 2019
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In the paper
§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > Introduction
“homozygous null RAC2 alleles (p.W56X)”
§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > Effects of RAC2 mutations on lymphocyte development
“recessive RAC2[W57X] null”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
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§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > Neutrophil analysis
“PMNs were incubated with AlexaFluor-488labeled Dextran (Molecular Probes) for 10 minutes.”
§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > Effects of RAC2 mutations on lymphocyte development
“Neutrophils from HC either fresh (left) or shipped along with the patient sample (middle) and Pt2 (right) were incubated with FITC-dextran for 15 minutes.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > Flow cytometric analysis of mouse peripheral blood
“antibodies against mouse CD45 (30-F11), CD19 (1D3), NK1.1 (PK136)”
§ IMMUNOBIOLOGY AND IMMUNOTHERAPY Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects > Effects of RAC2 mutations on lymphocyte development
“CD20 1 B cells (P value calculated using Student t test with Welch correction).”
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Real-time imaging reveals a role for macrophage protrusive motility in melanoma invasion
Ramakrishnan, G., Miskolci, V., Hunter, M. V., Giese, M. A., Münch, D., Hou, Y., Eliceiri, K. W., Lasarev, M. R., White, R. M., & Huttenlocher, A. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202403096 · Cited by 8
Li, X., Guo, Y., Deng, X., Jiao, Y., Hao, H., Dong, Q., Sun, H., & Han, S. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.119757 · Cited by 8
RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity
Guo, H., Hu, J., Wang, Z., Xu, F., Liu, Y., Cui, L., Zhang, H., Xie, C., Yao, R., Jin, H., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010931 · Cited by 7
Lauri, A., Fasano, G., Venditti, M., Dallapiccola, B., & Tartaglia, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.642235 · Cited by 7
Dupré, L., Castanon, I., & Boztuǧ, K. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-025-01214-w · Cited by 6
Paradigm Shifts in the History of Nox2 and Its Regulators: An Appreciative Critique
Pick, E. (2023) · Springer eBooks · doi:10.1007/978-3-031-23752-2_1 · Cited by 4
A Next-Generation Sequencing Test for Severe Congenital Neutropenia
McNulty, S. N., Evenson, M. J., Riley, M., Yoest, J. M., Corliss, M. M., Heusel, J. W., Duncavage, E. J., & Pfeifer, J. D. (2020) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2020.10.014 · Cited by 4
Recent advances in understanding inherited deficiencies in immunity to infections
Constantine, G. M., & Lionakis, M. S. (2020) · F1000Research · doi:10.12688/f1000research.22036.1 · Cited by 4
Self-citationXu, K., Jiang, P., Chen, Z., Gu, X., & Zhang, T. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155264 · Cited by 3
Congenital Defects of Phagocytes
Bogaert, D. J., & Haerynck, F. (2021) · Rare diseases of the immune system · doi:10.1007/978-3-030-70107-9_7 · Cited by 3
Lisco, A., Freeman, A. F., & Sereti, I. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-816768-7.00014-4 · Cited by 2
Case Report: Profound newborn leukopenia related to a novel RAC2 variant
Hall, G., Donkó, Á., Pratt, C. M., Kim-Chang, J. J., Martin, P. L., Stallings, A. P., Sleasman, J. W., Holland, S. M., Hsu, A. P., Leto, T. L., et al. (2024) · Frontiers in Pediatrics · doi:10.3389/fped.2024.1365187 · Cited by 2
Self-citationRubin, T. S., Williams, K. W., & Lawrence, M. G. (2024) · Wiley eBooks · doi:10.1002/9781683674023.ch66 · Cited by 2
Bolkov, M. A., Тузанкина, И. А., Shinwari, K., & Cheremokhin, D. A. (2021) · Russian Journal of Immunology · doi:10.46235/1028-7221-975-tir · Cited by 2
Dispensable role of Rac1 and Rac3 after cochlear hair cell specification
Nakamura, T., Sakaguchi, H., Mohri, H., Ninoyu, Y., Goto, A., Yamaguchi, T., Hishikawa, Y., Matsuda, M., Saito, N., & Ueyama, T. (2023) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02317-4 · Cited by 1
Allergic manifestations of actinopathies: A review
Gard, C. N., Freigeh, G. E., & Janssen, E. (2025) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2025.06.030 · Cited by 1
Yu, L., Zhou, B., Liu, W., Li, W., Wei, Q., Zhang, Y., Li, C., Li, W., Li, Y., Li, G., et al. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102232 · Cited by 1
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Congenital defects of phagocytes
Rezaei, N., Ghaffari, J., Khalili, A., Dabbaghzadeh, A., Ghaffari, N., Abolhassani, H., Seppänen, M. R. J., & Ehlayel, M. S. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-821028-4.00004-x · Cited by 1
Etzioni, A. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-816768-7.00036-3 · Cited by 1
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MBBS, F. B. J. B. (2021) · Wiley eBooks · doi:10.1002/9781119820307.ch6 · Cited by 1
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Ouyang, P., Wu, W., Li, R., Zhou, X., & Li, T. (2021) · American Journal of Internal Medicine · doi:10.11648/j.ajim.20210901.16
Grumach, A. S. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.737232141.793571790
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Momtazmanesh, S., & Rezaei, N. (2021) · Springer eBooks · doi:10.1007/978-3-319-66816-1_81-1
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A Novel Gain‐of‐Function RAC2 Variant (p.Y64H) Associated With Lymphopenia and Leukopenia
Haliloğlu, Y., Boyer, L., Doye, A., Gök, V., Bişgin, A., Özcan, A., Canatan, H., Yilmaz, E. A., Karakükçü, M., Eken, A., et al. (2026) · Pediatric Blood & Cancer · doi:10.1002/1545-5017.70106
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FRASER, D. D., Theofilou, V. I., Greenwell‐Wild, T., Brenchley, L., Kanasi, E., Wang, C., & Moutsopoulos, N. M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.21.713286
High content cell imaging reveals actin cytoskeleton-mediated control of the immunological synapse
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NG2-targeting macrophages inhibit 3D invasion of patient-derived glioblastoma spheroidsPreprint
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RAC2 orchestrates immune cell actin remodeling and migration
Berthiaume Fox, K. A., Galvin, E. R., Gurtner, G. C., & Chen, K. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1917716
Human inborn errors of the phagocyte respiratory burst: Chronic granulomatous disease and beyond
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Metadata
- Authors
- Hsu, A. P., Donkó, A., Arrington, M. E., Swamydas, M., Fink, D., Das, A., Escobedo, O., Bonagura, V., Szabolcs, P., Steinberg, H. N., Bergerson, J., Skoskiewicz, A., Makhija, M., Davis, J., Foruraghi, L., Palmer, C., Fuleihan, R. L., Church, J. A., Bhandoola, A., Lionakis, M. S., Campbell, S., Leto, T. L., Kuhns, D. B., & Holland, S. M.
- Affiliations
- Immunopathogenesis Section and
- Molecular Defenses Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD;
- University of North Carolina at Chapel Hill (US)
- National Institutes of Health (US)
- Frederick National Laboratory for Cancer Research (US)
- Cohen Children's Medical Center (US)
- Children's Hospital of Pittsburgh (US)
- Northwell Health (US)
- Lurie Children's Hospital (US)
- University of Southern California (US)
- Corresponding author
- Arrington, Megan E.
- Swamydas, Muthulekha
- Fink, Danielle
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2019-05-02
- Volume
- 133
- Issue
- 18
- Pages
- 1977-1988
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC6497516
- OpenAlex
- W2911871438
- Semantic Scholar
- aa2b614639e30df532caa47818889672a7c2bba4
- Cited by
- 92
- References
- 47
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 10 · 2023: 11 · 2022: 13 · 2021: 16 · 2020: 19 · 2019: 4
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Health and Human Services (HHSN261200800001E)
- National Institutes of Health (#HHSN261200800001E)
- National Cancer Institute (HHSN261200800001C, P01CA203657, HHSN261200800001E))
- National Institute of General Medical Sciences (R35GM134962)
- National Institute of Allergy and Infectious Diseases (HHSN261200800001E, R21AI105987)
- National Institute of Dental and Craniofacial Research (R01DE017227)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Hematology › Blood disorders and treatments
- Keywords
- Rac2, gain-of-function mutations, T-cell lymphopenia, B-cell lymphopenia, immunodeficiency, neutrophil superoxide production, NADPH oxidase, p67phox, fMLP chemotaxis, macropinocytosis, actin cytoskeleton, GTPase-activating protein, GTP hydrolysis, recurrent respiratory infections, Rac1
- MeSH terms
- Gain of Function Mutation, RAC2 GTP-Binding Protein, Adolescent, Adult, Animals, Child, Preschool, Cytoskeleton, Female, Humans, Immunologic Deficiency Syndromes, Infant, Infant, Newborn, Lymphopenia, Mice, Inbred C57BL, Pedigree, rac GTP-Binding Proteins, Mice
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