AIOLOS, also known as IKZF3, is a transcription factor that is highly expressed in the lymphoid lineage and is critical for lymphocyte differentiation and development. Here, we report on 9 individuals from 3 unrelated families carrying AIOLOS variants Q402* or E82K, which led to AIOLOS haploinsufficiency through different mechanisms of action. Nonsense mutant Q402* displayed abnormal DNA binding, pericentromeric targeting, posttranscriptional modification, and transcriptome regulation. Structurally, the mutant lacked the AIOLOS zinc finger (ZF) 5-6 dimerization domain, but was still able to homodimerize with WT AIOLOS and negatively regulate DNA binding through ZF1, a previously unrecognized function for this domain. Missense mutant E82K showed overall normal AIOLOS functions; however, by affecting a redefined AIOLOS protein stability domain, it also led to haploinsufficiency. Patients with AIOLOS haploinsufficiency showed hypogammaglobulinemia, recurrent infections, autoimmunity, and allergy, but with incomplete clinical penetrance. Altogether, these data redefine the AIOLOS structure-function relationship and expand the spectrum of AIOLOS-associated diseases.

中文翻译：

---

疾病相关的 AIOLOS 变异通过单倍体不足导致免疫缺陷/失调，并重新定义 AIOLOS 功能域。


AIOLOS，也称为 IKZF3，是一种在淋巴谱系中高表达的转录因子，对于淋巴细胞的分化和发育至关重要。在此，我们报告了来自 3 个不相关家庭的 9 名个体携​​带 AIOLOS 变体 Q402* 或 E82K，这些人通过不同的作用机制导致 AIOLOS 单倍体不足。无义突变体 Q402* 显示异常的 DNA 结合、着丝粒周围靶向、转录后修饰和转录组调控。在结构上，该突变体缺乏 AIOLOS 锌指 (ZF) 5-6 二聚化结构域，但仍然能够与 WT AIOLOS 形成同二聚体，并通过 ZF1 负向调节 DNA 结合，这是该结构域以前未被识别的功能。错义突变体 E82K 显示 AIOLOS 功能总体正常；然而，通过影响重新定义的 AIOLOS 蛋白稳定结构域，它也导致了单倍体不足。 AIOLOS 单倍体不足的患者表现出低丙种球蛋白血症、反复感染、自身免疫和过敏，但临床外显率不完全。总而言之，这些数据重新定义了 AIOLOS 的结构-功能关系，并扩大了 AIOLOS 相关疾病的范围。