Alt. symbols: EN-7

Approved name: Rac family small GTPase 2
Alt. names: ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)

Location: 22q13.1: 37225270 - 37259594 (-)
Gene type: protein_coding, 8 transcripts.

Scores: LoFtool: 0.173000 | pLI: 0.87309232 | LOEUF: 0.284

HGNC: 9802

NCBI: 5880, RefSeq: NG_007288.1

Ensembl: ENSG00000128340.16

LRG_97 | Status: public

OMIM: 602049

Expression | ProteinAtlas

RAC2 encodes a plasma membrane-associated small Rho GTPase with expression limited to the hematopoietic lineages. In its active state, the protein binds a variety of effector proteins to activate a variety of cellular signaling pathways, including actin polymerization, cell migration, and formation of the phagocytic NADPH oxidase complex.

Both monoallelic and biallelic mutations in RAC2 have been associated with related immunodeficiency syndromes featuring defective neutrophil chemotaxis and other variable defects [MIM:608203, 618986, 618987] via several different pathophysiologies. Ambruso et al. (2000) first reported a de novo heterozygous p.D57N mutation in a boy with defective neutrophil chemotaxis and leukocytosis (PMID: 10758162). This mutation was subsequently shown to function as a dominant-negative inhibitory mutation at the cellular level (PMID: 10961859). Accetta et al. (2011) then reported another patient with the same mutation and similar phenotype, identified by the finding of low TRECs on newborn screen (PMID: 21167572). Hsu et al. (2019) and Smits et al. (2020) reported patients harboring de novo heterozygous p.E62K mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections (PMID: 30723080, 31382036). Neutrophils from these patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Unlike D57N, which bound preferentially to GDP, p.E62K was noted to favor the active GTP-bound state, resulting in impaired GTP hydrolysis and prolonged activation of downstream effectors – in other words, a dominant gain-of-function effect. Sharapova et al. (2019) also identified a p.N92T mutation with similar properties in a Ukrainian girl with lymphoid and myeloid defects (PMID: 31071452). Additional reports of patients carrying heterozygous gain-of-function mutations have recently been published by Lougaris et al. (2019) (PMID: 30654050) and Lagresle-Peyrou et al. (2021) (PMID: 30654050), with the latter noting bone marrow hypoplasia in association with a p.G12R mutation. Alkhairy et al. (2015) identified a homozygous p.W56* loss-of-function mutation in 2 Iranian siblings, born to consanguineous parents, affected by a CVID-like presentation involving recurrent sinopulmonary infections, glomerulonephritis, bronchiectasis, hypothyroidism with anti-TPO autoantibodies, other endocrine abnormalities, and urticaria (PMID: 25512081). Of note, both patients were affected by early-onset, progressive hypogammaglobulinemia but no clinical evidence to suggest neutrophil defects, though their neutrophils were indeed found to be abnormal on structural and functional studies. [Load More]