Abstract：
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 naïve 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.
摘要：
AIOLOS,IKAROS蛋白家族的重要成员,通过DNA结合和蛋白质-蛋白质相互作用在淋巴细胞发育和功能中起重要作用。IKZF3基因突变,编码AIOLOS，导致罕见的联合免疫缺陷，通常与感染和恶性肿瘤有关。在这项研究中,我们评估了一名1岁4个月大的女性患者，腹泻,未能茁壮成长。实验室调查显示T淋巴细胞和免疫球蛋白水平降低。通过全外显子组和桑格测序，我们在IKZF3中发现了一个从头突变(NM_012481；外显子5c.571G>C，p.Gly191Arg)，对应于编码蛋白AIOLOS的第三个DNA结合锌指区。值得注意的是,AIOLOSG191R突变的患者与同年龄的健康者相比，幼稚CD4+T细胞的近期胸腺外移减少，同时保持Th1，Th2，Th17，Treg的正常水平，和Tfh细胞。该突变还导致转换的记忆B细胞减少和CD23和IgM表达降低。体外研究表明，AIOLOSG191R不会影响AIOLOS的表达，但会损害其稳定性，DNA结合和着丝粒靶向。此外，AIOLOSG191R显示出相对于野生型蛋白的显性负作用。这种情况代表了AIOLOS的第三个DNA结合锌指区域中突变的第一个报道实例，突出了其在免疫细胞功能中的关键作用。
