Liang Zhang1,2, Ge Lv3,4,5, Yu Peng2,6, Lu Yang3,4,5, Junjie Chen3,4,5, Yunfei An3,4,5, Zhiyong Zhang3,4,5, Xuemei Tang3,4,5, Zhihui Li7,8, Xiaodong Zhao9,10,11. 1. Department of Nephrology, Rheumatology and Immunology, Hunan Children's Hospital, Changsha, Hunan, China. 2. The School of Pediatrics, Hengyang Medical School, University of South China, Hengyang, Hunan, China. 3. Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. 4. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China. 5. Division of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China. 6. Department of Pediatrics Research Institute, Hunan Children's Hospital, Changsha, Hunan, China. 7. Department of Nephrology, Rheumatology and Immunology, Hunan Children's Hospital, Changsha, Hunan, China. Lizh0731@aliyun.com. 8. The School of Pediatrics, Hengyang Medical School, University of South China, Hengyang, Hunan, China. Lizh0731@aliyun.com. 9. Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. zhaoxd530@aliyun.com. 10. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China. zhaoxd530@aliyun.com. 11. Division of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China. zhaoxd530@aliyun.com.
Abstract
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 naïve 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.
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 naïve 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.
Authors: D A Williams; W Tao; F Yang; C Kim; Y Gu; P Mansfield; J E Levine; B Petryniak; C W Derrow; C Harris; B Jia; Y Zheng; D R Ambruso; J B Lowe; S J Atkinson; M C Dinauer; L Boxer Journal: Blood Date: 2000-09-01 Impact factor: 22.113