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Cited by 85Protein Kinase Regulation and GTPase SignalingImmunodeficiency and Autoimmune DisordersProtein Tyrosine Phosphatases

The DOI matches its Crossref record; 89 of the 89 references it cites were found in a registry or an index; none of the 62 sources its claims cite is checked for support yet.

Rac GTPases in Human Diseases

Open access
Pai, Sung-Yun, Kim, Chaekyun, Williams, David A.·2010·Disease Markers
DOI 10.1155/2010/380291PMC PMC3835286
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Abstract

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.

Overview

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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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Integrity signals

Registry

Crossref · 10.1155/2010/380291

Cites

89 of 89 references verified0 citation errors · 0 not checkable

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Claims the paper makes

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Metadata

Authors
Pai, S.-Y., Kim, C., & Williams, D. A.
Affiliations
  • Boston Children's Hospital (US)
  • Inha University (KR)
Corresponding author
Williams, David A.
ORCID
Venue
Disease Markers
Publisher
Wiley
Published
2010
Volume
29
Issue
3-4
Pages
177-187
ISSN
  • 0278-0240 (ISSN-L)
  • 1875-8630
DOI
10.1155/2010/380291
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
Licence
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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