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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
plainSingle case- Asserted: passes — The authors put it forward as true.
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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
plainn = 3- Asserted: passes — The authors put it forward as true.
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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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“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 paper
“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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Claims other papers make about this one
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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.
In the paper
§ 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).”
Citations
Cites
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Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma
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RAS isoforms and mutations in cancer at a glance
Hobbs, G. A., Der, C. J., & Rossman, K. L. (2016) · Journal of Cell Science · doi:10.1242/jcs.182873 · Cited by 973
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Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells
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Regulation of Phagocyte Oxygen Radical Production by the GTP-Binding Protein Rac 2
Knaus, U. G., Heyworth, P. G., Evans, T., Curnutte, J. T., & Bokoch, G. M. (1991) · Science · doi:10.1126/science.1660188 · Cited by 525
Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation
Ambruso, D. R., Knall, C., Abell, A. N., Panepinto, J., Kurkchubasche, A., Thurman, G., Gonzalez-Aller, C., Hiester, A., deBoer, M., Harbeck, R. J., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.080074897 · Cited by 407
Cdc42, Rac1, and Rac2 Display Distinct Patterns of Activation during Phagocytosis
Hoppe, A. D., & Swanson, J. A. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-11-0847 · Cited by 365
Organ-Specific Innate Immune Responses in a Mouse Model of Invasive Candidiasis
Lionakis, M. S., Lim, J. K., Lee, C.-C. R., & Murphy, P. M. (2011) · Journal of Innate Immunity · doi:10.1159/000321157 · Cited by 302
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Self-citationA novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function
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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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