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Rac GTPases in Human Diseases
Open accessAbstract
Rho GTPases are members of the Ras superfamily of GTPases that regulate a wide variety of cellular functions. While Rho GTPase pathways have been implicated in various pathological conditions in humans, to date coding mutations in only the hematopoietic specific GTPase,RAC2, have been found to cause a human disease, a severe phagocytic immunodeficiency characterized by life-threatening infections in infancy. Interestingly, the phenotype was predicted by a mouse knock-out of RAC2 and resembles leukocyte adhesion deficiency (LAD). Here we review Rho GTPases with a specific focus on Rac GTPases. In particular, we discuss a new understanding of the unique and overlapping roles of Rac2 in blood cells that has developed since the generation of mice deficient in Rac1, Rac2 and Rac3 proteins. We propose that Rac2 mutations leading to disease be termed LAD type IV.
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TL;DR
This review summarizes the roles of Rho family GTPases, focusing on the Rac subfamily, in blood cell biology and human disease. It argues that the two reported cases of dominant-negative RAC2 mutation causing severe phagocytic immunodeficiency—resembling leukocyte adhesion deficiency—should be termed LAD type IV.
Key findings
- To date, coding mutations in only one Rho GTPase, the hematopoietic-specific RAC2, have been found to cause human disease; mutations in the first intron of RHOH have been implicated in B cell malignancies.
- Two patients with a c.169G>A mutation predicting p.Asp57Asn (D57N) in RAC2 presented as newborns with infection around the umbilical stump, neutrophilia/leukocytosis, absent pus, and recurrent life-threatening bacterial infections; both required allogeneic hematopoietic stem cell transplantation.
- Patient cells recapitulated the Rac2−/− mouse phenotype: defects in chemotaxis, migration, F-actin formation, and selective NADPH oxidase defects (a CGD feature), with normal CD11b/CD18 expression ruling out LAD type I.
- The second patient, identified by newborn screening for SCID, had complete absence of TREC (0–4/µL vs. mean 225/µL in normal newborns; cutoff <25/µL) but only mild T cell lymphopenia (1434/µL) with increased CD45RO expression.
- The authors propose the term LAD type IV for this disease.
Methods
- Narrative review of Rho/Rac GTPase biology, integrating in vitro mutant studies, gene-targeted mouse models (Rac1, Rac2, Rac3 knockouts and conditional/double knockouts), and clinical data from two human RAC2 mutation cases.
- Includes a summary table (Table 1) comparing laboratory abnormalities across Case 1, Case 2, and the Rac2−/− mouse (neutrophil count, exudate formation, NADPH oxidase responses, adhesion, chemotaxis, F-actin formation, phagocytosis, degranulation).
- No primary experimental data are generated; the second patient's data are cited as unpublished (courtesy of J. Routes, J. Verbsky et al.).
Limitations
- The paper notes that dominant-negative mutant studies suffer from non-specific effects and expression-level dependence, and that cell-line work may not reflect primary cells; the second human case relies partly on unpublished data.
- The authors state that why TREC are disproportionately low in the mild lymphopenia case "remains unclear," and that the human lymphocyte phenotype is less severe than in doubly deficient mice, possibly reflecting null vs. dominant-negative differences.
- Evident from the text: only two human RAC2 cases are described, and the LAD type IV nomenclature is a proposal rather than an established classification.
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40 Sources not found · 16 Own result · 13 Own interpretation · 1 Own method · 1 No basis given
In the paper
“observed abnormal myeloid development in vitro after transduction of HSC/P with the DN D57NRac2 mutant, which most likely inhibits Rac3 in addition to Rac1 and Rac2 [76].”
What the sources say
- Not matchedcites [76]
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In the paper
“The clinical presentation of both patients was charac- terized by defects in neutrophiladhesion and migration.”
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In the paper
“The findings from this case have now been corroborated by a second case, which came to attention in the course of universal newborn screen- ing in Wisconsin for severe combined immunodeficien- cy (SCID) [69] and unpublished data (courtesy of J. Routes, J. Verbsky et. al.).”
What the sources say
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plainstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“Many of these findings were also seen in the second patient.”
plainstates an associationSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“Both children were found to have a c.169G>A mu- tation that results in a predicted protein change of p.Asp57Asn (D57N).”
plainstates a cause- Asserted: passes — The authors put it forward as true.
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In the paper
“The Rho proteins can be divided into 6 families based on sequence homology, protein domains and function.”
“These include Rac,RhoA, Cdc42,TC10 and TCL, Rnd, the Rho BTB subset and the Miro subfamily.”
Citations
Cites
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Changes in thymic function with age and during the treatment of HIV infection
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PROTEIN PRENYLATION: Molecular Mechanisms and Functional Consequences
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Cited by
Practice parameter for the diagnosis and management of primary immunodeficiency
Bonilla, F. A., Khan, D. A., Ballas, Z. K., Chinen, J., Frank, M. M., Hsu, J. T., Keller, M. D., Kobrynski, L. J., Komarow, H. D., Mazer, B. D., et al. (2015) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2015.04.049 · Cited by 832
Hall, A. (2012) · Biochemical Society Transactions · doi:10.1042/bst20120103 · Cited by 579
Characterization of EHop-016, Novel Small Molecule Inhibitor of Rac GTPase
Montalvo-Ortiz, B. L., Castillo-Pichardo, L., Hernández, E., Humphries-Bickley, T., De La Mota-Peynado, A., Cubano, L. A., Vlaar, C. P., & Dharmawardhane, S. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.334524 · Cited by 213
Nieborowska-Skorska, M., Kopinski, P. K., Ray, R., Hoser, G., Ngaba, D., Flis, S., Cramer, K., Reddy, M. M., Koptyra, M., Penserga, T., et al. (2012) · Blood · doi:10.1182/blood-2011-10-385658 · Cited by 177
Self-citationDirect multiplex imaging and optogenetics of Rho GTPases enabled by near-infrared FRET
Shcherbakova, D. M., Cammer, N. C., Huisman, T. M., Verkhusha, V. V., & Hodgson, L. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0044-1 · Cited by 154
Metadata
- Authors
- Pai, S.-Y., Kim, C., & Williams, D. A.
- Affiliations
- Boston Children's Hospital (US)
- Inha University (KR)
- Corresponding author
- Williams, David A.
- Venue
- Disease Markers
- Publisher
- Wiley
- Published
- 2010
- Volume
- 29
- Issue
- 3-4
- Pages
- 177-187
- ISSN
- 0278-0240 (ISSN-L)
- 1875-8630
- PMC
- PMC3835286
- OpenAlex
- W4239395424
- Cited by
- 85
- References
- 89
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 5 · 2016: 8 · 2015: 9 · 2014: 6 · 2013: 8 · 2012: 6
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Disease Markers (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- PubMed
- Funders
- National Institutes of Health (DK062757, CA113969, AI083907, A080244)
- Children’s Hospital Boston Translational Investigator Service (SYP) (DK062757, CA113969, AI083907, A080244)
- Health Care Medical Technology R&D Projects (DK062757, CA113969, AI083907, A080244)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Rac GTPase, Rho GTPases, Rac2, Rac1, RAC3, hematopoietic cells, Ras superfamily
- MeSH terms
- Animals, Hematopoietic System, Humans, Infant, Mutation, Opportunistic Infections, Phagocytes, Signal Transduction, Mice, Knockout, Leukocyte-Adhesion Deficiency Syndrome, Protein Isoforms, rac GTP-Binding Proteins, Mice, Genetic Association Studies
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