A Novel RAC2 Mutation Causing Combined Immunodeficiency

作者全名："Zhang, Liang; Lv, Ge; Peng, Yu; Yang, Lu; Chen, Junjie; An, Yunfei; Zhang, Zhiyong; Tang, Xuemei; Li, Zhihui; Zhao, Xiaodong"

作者地址："[Zhang, Liang; Li, Zhihui] Hunan Childrens Hosp, Dept Nephrol Rheumatol & Immunol, Changsha, Hunan, Peoples R China; [Zhang, Liang; Peng, Yu; Li, Zhihui] Univ South China, Sch Pediat, Hengyang Med Sch, Hengyang, Hunan, Peoples R China; [Lv, Ge; Yang, Lu; Chen, Junjie; An, Yunfei; Zhang, Zhiyong; Tang, Xuemei; Zhao, Xiaodong] Chongqing Med Univ, Childrens Hosp, Key Lab Child Dev & Disorders,China Int Sci & Tec, Dept Pediat Res Inst,Minist Educ,Natl Clin Res Ct, Chongqing, Peoples R China; [Lv, Ge; Yang, Lu; Chen, Junjie; An, Yunfei; Zhang, Zhiyong; Tang, Xuemei; Zhao, Xiaodong] Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China; [Lv, Ge; Yang, Lu; Chen, Junjie; An, Yunfei; Zhang, Zhiyong; Tang, Xuemei; Zhao, Xiaodong] Chongqing Med Univ, Div Rheumatol & Immunol, Childrens Hosp, Chongqing, Peoples R China; [Peng, Yu] Hunan Childrens Hosp, Dept Pediat Res Inst, Changsha, Hunan, Peoples R China"

通信作者："Li, ZH (通讯作者)，Hunan Childrens Hosp, Dept Nephrol Rheumatol & Immunol, Changsha, Hunan, Peoples R China.; Li, ZH (通讯作者)，Univ South China, Sch Pediat, Hengyang Med Sch, Hengyang, Hunan, Peoples R China.; Zhao, XD (通讯作者)，Chongqing Med Univ, Childrens Hosp, Key Lab Child Dev & Disorders,China Int Sci & Tec, Dept Pediat Res Inst,Minist Educ,Natl Clin Res Ct, Chongqing, Peoples R China.; Zhao, XD (通讯作者)，Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China.; Zhao, XD (通讯作者)，Chongqing Med Univ, Div Rheumatol & Immunol, Childrens Hosp, Chongqing, Peoples R China."

来源：JOURNAL OF CLINICAL IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000865212300001

JCR分区：Q1

影响因子：9.1

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Ras-related C3 botulinum toxin substrate 2 (RAC2); Combined immunodeficiency; gain-of-function mutation; penetrance

摘要："Purpose 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 immunodeficiency, with complete penetrance. Here, we report a novel heterozygous missense mutation in RAC2 with incomplete penetrance, and the associated phenotypes, in a Chinese family. Methods Immunological phenotype was detected by flow 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 confirmed by Sanger sequencing. Results The 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 naive CD4(+) and CD8(+) T cells, an inverted CD4(+)/CD8(+) ratio, and low TREC and KREC numbers. The mutation resulted in increased production of reactive oxygen species, while impaired actin polarization in neutrophils; diminished proliferative responses, increased cytokine production and a dysregulated phenotype in T lymphocytes; as well as accelerated apoptosis and hyperactivity of AKT in HL-60 human leukemia cells. WES identified a c.44G > A mutation in RAC2 resulting in a p.G15D substitution. Despite sharing the same mutation as the proband, her father suffered from recurrent respiratory infections and bronchiectasis, and had similar immunological defects, whereas her sister was apparently healthy, other than cutaneous human papillomavirus infections, and only mild immunological defects were detected preliminarily. Conclusions Our findings broaden the clinical and genetic spectra of RAC2 mutations and underline the importance of RAC2 gain-of-function mutations with complete or incomplete penetrance."

基金机构：Postgraduate Tutor Team Project of Chongqing Municipal Education Commission Education Research and Development Program of Chongqing [2019-9-66]; Talent Program of Hunan Children's Hospital [1233]; Clinical Research (Translation) Center of Hunan Children's Hospital

基金资助正文："This work was supported by the Postgraduate Tutor Team Project of Chongqing Municipal Education Commission Education Research and Development Program of Chongqing: 2019-9-66). L.Z. was also supported by the Talent Program of Hunan Children's Hospital (grant number: 1233), and supported by the Clinical Research (Translation) Center of Hunan Children's Hospital."