Identification and Functional Analysis of a <i>de novo IKZF3</i> Mutation in a Pediatric Patient with Combined Immunodeficiency

作者全名：Shi, Xiaoqi; Cao, Xiuli; Huang, Meiying; Zhang, Pingping; Yang, Guangli; Ren, Aiyan; Dai, Xin; Chen, Ran; Yang, Zhigang; Cai, Zeyuan; Chen, Yan; Zhao, Xiaodong; Huang, Pei; Du, Zuochen

作者地址：[Shi, Xiaoqi; Cao, Xiuli; Huang, Meiying; Zhang, Pingping; Yang, Guangli; Ren, Aiyan; Cai, Zeyuan; Chen, Yan; Huang, Pei; Du, Zuochen] Zunyi Med Univ, Dept Pediat, Affiliated Hosp, Zunyi 563003, Guizhou, Peoples R China; [Shi, Xiaoqi; Cao, Xiuli; Huang, Meiying; Zhang, Pingping; Yang, Guangli; Ren, Aiyan; Cai, Zeyuan; Chen, Yan; Huang, Pei; Du, Zuochen] Guizhou Childrens Hosp, Dept Pediat, Zunyi, Peoples R China; [Shi, Xiaoqi; Cao, Xiuli; Huang, Meiying; Zhang, Pingping; Yang, Guangli; Ren, Aiyan; Cai, Zeyuan; Chen, Yan; Huang, Pei; Du, Zuochen] Zunyi Med Univ, Collaborat Innovat Ctr Tissue Injury Repair & Rege, Zunyi, Peoples R China; [Dai, Xin; Yang, Zhigang] Guangdong Med Univ, Zhanjiang Cent Hosp, Zhanjiang Inst Clin Med, Zhanjiang, Peoples R China; [Dai, Xin; Yang, Zhigang] Cent Peoples Hosp Zhanjiang, Dept Hematol, Zhanjiang, Peoples R China; [Chen, Ran; Zhao, Xiaodong] Childrens Hosp Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders Chongqing, Chongqing, Peoples R China

通信作者：Huang, P; Du, ZC (通讯作者)，Zunyi Med Univ, Dept Pediat, Affiliated Hosp, Zunyi 563003, Guizhou, Peoples R China.; Huang, P; Du, ZC (通讯作者)，Guizhou Childrens Hosp, Dept Pediat, Zunyi, Peoples R China.; Huang, P; Du, ZC (通讯作者)，Zunyi Med Univ, Collaborat Innovat Ctr Tissue Injury Repair & Rege, Zunyi, Peoples R China.

来源：JOURNAL OF CLINICAL IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001227231000008

JCR分区：Q1

影响因子：7.2

年份：2024

卷号：44

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：IKZF3; Inborn Errors of Immunity; Combined Immunodeficiency; AIOLOS

摘要：AIOLOS, a vital member of the IKAROS protein family, plays a significant role in lymphocyte development and function through DNA binding and protein-protein interactions. Mutations in the IKZF3 gene, which encodes AIOLOS, lead to a rare combined immunodeficiency often linked with infections and malignancy. In this study, we evaluated a 1-year-4-month-old female patient presenting with recurrent infections, diarrhea, and failure to thrive. Laboratory investigations revealed decreased T lymphocyte and immunoglobulin levels. Through whole-exome and Sanger sequencing, we discovered a de novo mutation in IKZF3 (NM_012481; exon 5 c.571G > C, p.Gly191Arg), corresponding to the third DNA-binding zinc finger region of the encoded protein AIOLOS. Notably, the patient with the AIOLOS G191R mutation showed reduced recent thymic emigrants in na & iuml;ve CD4+T cells compared to healthy counterparts of the same age, while maintaining normal levels of Th1, Th2, Th17, Treg, and Tfh cells. This mutation also resulted in decreased switched memory B cells and lower CD23 and IgM expression. In vitro studies revealed that AIOLOS G191R does not impact the expression of AIOLOS but compromises its stability, DNA binding and pericentromeric targeting. Furthermore, AIOLOS G191R demonstrated a dominant-negative effect over the wild-type protein. This case represents the first reported instance of a mutation in the third DNA-binding zinc finger region of AIOLOS highlighting its pivotal role in immune cell functionality.

基金机构：National Natural Science Foundation of China

基金资助正文：No Statement Available