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

作者全名："Zhang, Liang; Chen, Zhi; Li, Wenyan; Liu, Qiao; Wang, Yanping; Chen, Xuemei; Tian, Zhirui; Yang, Qiuyun; An, Yunfei; Zhang, Zhiyong; Mao, Huawei; Tang, Xuemei; Lv, Ge; Zhao, Xiaodong"

作者地址："[Zhang, Liang; Chen, Zhi; Li, Wenyan; Liu, Qiao; Wang, Yanping; Chen, Xuemei; Tian, Zhirui; Yang, Qiuyun; An, Yunfei; Zhang, Zhiyong; Mao, Huawei; Tang, Xuemei; Lv, Ge; Zhao, Xiaodong] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders Chongqin, Key Lab Child Dev & Disorders, Dept Pediat,Res Inst,Minist Educ, Chongqing, Peoples R China; [Zhang, Liang; Chen, Zhi; Li, Wenyan; Liu, Qiao; Wang, Yanping; Chen, Xuemei; Tian, Zhirui; Yang, Qiuyun; An, Yunfei; Zhang, Zhiyong; Mao, Huawei; Tang, Xuemei; Lv, Ge; Zhao, Xiaodong] Chongqing Med Univ, China Int Sci & Technol Cooperat Base Child Dev &, Childrens Hosp, Chongqing, Peoples R China; [Zhang, Liang; Chen, Zhi; Li, Wenyan; Liu, Qiao; Wang, Yanping; Chen, Xuemei; Tian, Zhirui; Yang, Qiuyun; An, Yunfei; Zhang, Zhiyong; Mao, Huawei; Tang, Xuemei; Lv, Ge; Zhao, Xiaodong] Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China; [Zhang, Liang; Chen, Zhi; Li, Wenyan; Liu, Qiao; Wang, Yanping; Chen, Xuemei; Tian, Zhirui; Yang, Qiuyun; An, Yunfei; Zhang, Zhiyong; Mao, Huawei; Tang, Xuemei; Lv, Ge; Zhao, Xiaodong] Chongqing Med Univ, Div Rheumatol & Immunol, Childrens Hosp, Chongqing, Peoples R China; [Zhang, Liang] Univ South China, Dept Nephrol Rheumatol & Immunol, Hunan Childrens Hosp, Paediat Acad, Changsha, Hunan, Peoples R China; [Chen, Zhi] Univ Elect Sci & Technol China, Chengdu Womens & Childrens Cent Hosp, Sch Med, Dept Immunol, Chengdu, Peoples R China"

通信作者："Lv, G; Zhao, XD (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders Chongqin, Key Lab Child Dev & Disorders, Dept Pediat,Res Inst,Minist Educ, Chongqing, Peoples R China.; Lv, G; Zhao, XD (通讯作者)，Chongqing Med Univ, China Int Sci & Technol Cooperat Base Child Dev &, Childrens Hosp, Chongqing, Peoples R China.; Lv, G; Zhao, XD (通讯作者)，Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China.; Lv, G; 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:000798471100001

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; Apoptosis; Polarization

摘要："Ras-related C3 botulinum toxin substrate 2 (RAC2) is a GTPase exclusively expressed in hematopoietic cells that acts as a pivotal regulator of several aspects of cell behavior via various cellular processes. RAC2 undergoes a tightly regulated GTP-binding/GTP-hydrolysis cycle, enabling it to function as a molecular switch. Mutations in RAC2 have been identified in 18 patients with different forms of primary immunodeficiency, ranging from phagocyte defects caused by dominant negative mutations to common variable immunodeficiency resulting from autosomal recessive loss-of-function mutations, or severe combined immunodeficiency due to dominant activating gain-of-function mutations. Here, we describe an 11-year-old girl with combined immunodeficiency presenting with recurrent respiratory infections and bronchiectasis. Immunological investigations revealed low T-cell receptor excision circle/K-deleting recombination excision circles numbers, lymphopenia, and low serum immunoglobulin G. Targeted next-generation sequencing identified a novel heterozygous mutation in RAC2, c.86C > G (p.P29R), located in the highly conserved Switch I domain. The mutation resulted in enhanced reactive oxygen species production, elevated F-actin content, and increased RAC2 protein expression in neutrophils, as well as increased cytokine production and a dysregulated phenotype in T lymphocytes. Furthermore, the dominant activating RAC2 mutation led to accelerated apoptosis with augmented intracellular active caspase 3, impaired actin polarization in lymphocytes and neutrophils, and diminished RAC2 polarization in neutrophils. We present a novel RAC2 gain-of-function mutation with implications for immunodeficiency and linked to functional dysregulation, including abnormal apoptosis and cell polarization arising from altered RAC2 expression. Thus, our findings broaden the spectrum of known RAC2 mutations and their underlying mechanisms."

基金机构：Postgraduate Tutor Team Project of Chongqing Municipal Education Commission (Education Research and Development Program of Chongqing) [2019-9-66]

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).