Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation

Zhang, Liang; Chen, Zhi; Li, Wenyan; Li, Qiao; Wang, Yanping; Tian, Zhirui; Yang, Qixiang; An, Yi; Zhang, Zhiyong; Mao, Huawei; Tang, Xuemei; Lv, Ge; Zhao, Xiaodong

doi:10.1007/s10875-022-01288-4

Cited by 8 publications

(13 citation statements)

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“…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].…”

Section: Discussionsupporting

confidence: 77%

“…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.…”

Section: Introductionmentioning

confidence: 74%

“…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.…”

Section: Literature Reviewmentioning

confidence: 99%

“…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].…”

Section: Literature Reviewmentioning

confidence: 99%

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Gain-of-function RAC2 variants presenting as autoinflammatory phenotypes

Zhang

et al. 2023

Preprint

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Background An expanded spectrum of gain-of-function (GOF) mutations in Ras-related C3 botulinum toxin substrate 2 (RAC2) causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID), which present with various phenotypes; these immunodeficiencies are characterized by severe lymphopenia, recurrent sinopulmonary infections, bronchiectasis, invasive viral infections, or severe bone marrow hypoplasia. Autoinflammatory features are rarely reported. Method We describe the cases of two girls presenting with novel autoinflammatory phenotypes associated with GOF RAC2 variants. An up-to-date review of the literature was conducted to explore the various spectra of clinical manifestations in patients with GOF RAC2 variants. Results One patient presented with vasculitis and leg ulcers, whereas the other presented with juvenile idiopathic arthritis and severe uveitis. Conclusion Our data extend the spectrum of the clinical presentation of GOF RAC2 variants, which may be associated with autoinflammation, highlighting novel and unusual clinical phenotypes.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 74%

Section: Literature Reviewmentioning

confidence: 99%

Section: Literature Reviewmentioning

confidence: 99%

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Gain-of-function RAC2 variants presenting as autoinflammatory phenotypes

Zhang

et al. 2023

Preprint

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“…2 Dominant-activating (DA) mutations in the RAC2 gene were first described in 2019 and to date, seven unique DA mutations have been identified. [3][4][5][6][7][8][9][10] Affected individuals present with (severe) combined immunodeficiency (CID) syndrome with some requiring haematopoietic stem cell transplantation (HSCT). Herein, we present the features of seven individuals from the same kindred with a novel DA variant in RAC2 (c.62T > G, p.I21S) (Figure 1a).…”

Section: Introductionmentioning

confidence: 99%

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

Ashby,

Chan,

Winterbourn

et al. 2024

Clin & Trans Imm

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ObjectivesDominant‐activating (DA) lesions in RAC2 have been reported in 18 individuals to date. Some have required haematopoietic stem cell transplantation (HSCT) for their (severe) combined immunodeficiency syndrome phenotype. We aimed to investigate clinical and cellular features of a kindred harbouring a novel variant in RAC2 p.Ile21Ser (I21S) to better understand DA lesions' phenotypic spectrum.MethodsClinical and immunological information was collated for seven living individuals from the same kindred with RAC2 p.I21S. We evaluated neutrophil morphology, RAC2 protein expression and superoxide production using freshly isolated neutrophils stimulated with phorbol‐12‐myristate‐13‐acetate (PMA) and N‐formyl‐MetLeuPhe (fMLP).ResultsPatient 1 (P1, aged 11, male) has a history of bacterial suppurative otitis media, viral and bacterial cutaneous infections. P1's siblings (P2, P3), mother (P4), maternal aunt (P5) and uncle (P6) have similar infection histories. P1's maternal cousin (P7) presented with Burkitt's lymphoma at age 9. All affected individuals are alive and none has required HSCT to date. They have chronic lymphopenia affecting the CD4+T and B‐cell compartments. P1–3 have isolated reduction in IgM levels whereas the adults universally have normal immunoglobulins. Specific antibody responses are preserved. Affected individuals have neutrophil vacuolation, and their neutrophils have enhanced superoxide production compared to healthy controls.ConclusionRAC2 p.I21S is an activating variant causing notable morphological and functional abnormalities similar to other reported DA mutations. This novel variant expands the broad clinical phenotypic spectrum of RAC2 DA lesions, emphasising the need to tailor clinical management according to patients' disease phenotype and severity.

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A Novel RAC2 Mutation Causing Combined Immunodeficiency

Zhang

et al. 2022

J Clin Immunol

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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.

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Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation

Cited by 8 publications

References 53 publications

Gain-of-function RAC2 variants presenting as autoinflammatory phenotypes

Gain-of-function RAC2 variants presenting as autoinflammatory phenotypes

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

A Novel RAC2 Mutation Causing Combined Immunodeficiency

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