Rac GTPases in Human Diseases

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• No primary experimental data are generated; the second patient's data are cited as unpublished (courtesy of J. Routes, J. Verbsky et al.).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dependence, and that cell-line work may not reflect primary cells; the second human case relies partly on unpublished data.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.