A Novel RAC2 Mutation Causing Combined Immunodeficiency

Abstract

Ras-related C3 botulinum toxin substrate 2 (RAC2) acts as a molecular switch and has crucial roles in cell signaling and actin dynamics. A broad spectrum of genetic RAC2 mutations can cause various types of primary immunode ciency, with complete penetrance. Here, we report a novel heterozygous missense mutation in RAC2 and the associated phenotypes in a Chinese family. MethodsImmunological phenotype was detected by ow cytometry. T-cell receptor excision circles (TRECs) and K-deleting recombination excision circles (KRECs) were assessed by real-time quantitative PCR. Gene mutations were detected by whole-exome sequencing (WES) and con rmed by Sanger sequencing. ResultsThe proband was an 11-year-old girl who presented with recurrent respiratory infections, bronchiectasis, persistent Epstein-Barr virus viremia, infectious mononucleosis, encephalitis, and cutaneous human papillomavirus infections.Laboratory analyses revealed increased serum IgG and decreased IgM levels, reduced naïve CD4 + and CD8 + T cells, an inverted CD4 + /CD8 + ratio, and low TREC and KREC numbers. WES identi ed a c.44G > A mutation in RAC2 resulting in a p.G15D substitution. The proband's father suffered with recurrent respiratory infections and bronchiectasis, while her sister was apparently healthy, other than cutaneous human papillomavirus infections, despite both sharing the same mutation as the proband. ConclusionsOur ndings broaden the clinical and genetic spectra of RAC2 mutations and underline the importance of RAC2 gain-offunction mutations with complete or incomplete penetrance.

Gain-of-function RAC2 variants presenting as autoinflammatory phenotypes

“…There is a direct link between RAC2 and production of ROS, TNF-α, IL-1, IFN, and NF-κB signaling [36-39]; indeed, neutrophils are a key component of the pathogenesis of AIDs, found mainly in affected tissues such as the in amed joints, skin lesions, vasculitis and uveitis [40][41][42][43], and the markers of neutrophilic in ammation, such as S100A12, S100A8, and S100A9, are eleveted in juvenile idiopathic arthritis and AIDs [44][45][46], which was also seen in our patient 1 by single-cell RNAseq [23]; RAC2 recruits neutrophils to in amed tissues, including the joints in those with rheumatoid arthritis or the blood vessels in those with vasculitis [47]. Furthermore, a dysregulated phenotype in T lymphocytes skews the immunopro le toward Th1/17 subsets, which were also detected in our patients [9,10]. This skewing can trigger pathogenesis of juvenile idiopathic arthritis, uveitis, and vasculitis [48][49][50].…”

“…Recently, we reported two Chinese families with GOF RAC2 variants, i.e., p.P29R and p.G15D substitutions [9,10]. Here, we report these two affected girls presented with novel autoin ammatory phenotypes during follow-up: one with livedo reticularis followed by vasculitis and ulcers on the leg, and the other with juvenile idiopathic arthritis and severe uveitis leading to severe loss of vision.…”

“…Herein, neither mutation were collected or analyzed in detail, only RAC2 GOF germline mutations were focused on. A literature review identi ed eight relevant reports enrolling 18 cases in total [9,10,[17][18][19][20][21][22]. The mechanisms underlying diverse RAC2 GOF mutations leading to heterogeneous clinical phenotypes and immunological defects may be attributed, at least in part, to the position of the amino acid substitution, which ultimately determines the activity of the RAC2-GTP form; mutations resulting in a constitutively active RAC2-GTP form typically present with a more severe phenotype than those resulting in a transiently active form [21,22].…”

“…3b and Table 2). Predominant immunologic features include T and B cell lymphopenia associated with increased ratios of transitional B cells and effector/memory T cells, decreased serum IgG and IgM levels, and impaired lymphocyte proliferation upon stimulation (Table 3) [9,10,[17][18][19][20][21][22][23]. In addition, some patients are characterized by neutropenia associated with increased ROS production after stimulus and enlarged macropinocytotic vesicles, which are the preliminary features that distinguished RAC2 GOF germline mutations from its autosomal dominant negative mutation.…”

Phenotypic spectrum in a family with a novel RAC2 p.I21S dominant‐activating mutation

“…Reported effects of the mutated RAC2 protein in lymphoid cells include F-actin accumulation, impaired actin polymerisation, dysregulated cytokine production, accumulation of senescent CD8 + CD57 + T cells, accelerated T-and B-lymphocyte apoptosis, and functional and developmental alteration in NK cells. 4,9,10 Additionally, we observed in our patients an expanded gamma-delta double-negative T-cell population. Gamma-delta T cells are generally thought to serve as the first line of defence in epithelial and mucosal tissues owing to their ability to rapidly respond to pathogens in a major histocompatibility complex independent manner.…”