Immune dysregulation often presents as autoimmunity, inflammation and/or lymphoproliferation. Several germline genetic defects have been associated with immune dysregulation including heterozygous gain-of-function (GOF) mutations in , an essential transcription factor for hematopoiesis containing zinc finger domains (ZFs). However, in a large part of patients the genetic origin of their immunedysregulation remains undetermined. A family with two members presenting immune dysregulation signs was studied to identify the genetic cause of their disease. Whole exome sequencing, analysis of immunological parameters, functional assays including western blotting, EMSA during cell cycle and T helper differentiation were performed. The two patients carried a novel heterozygous mutation in (IKZF1). 1 heterozygous mutations have been previously shown to be responsible of several distinct human immunological diseases by directly impacting the ability of ZFs to bind to DNA or to dimerize. Herein, we showed that the IKZF1 which is outside the ZFs caused impaired phosphorylation of IKZF1 resulting in enhanced DNA-binding ability at the S phase of cell cycle, reduction of the G1-S phase transition and decreased proliferation. Confirming these data, similar functional alterations were observed with IKZF1, but not with IKZF1 mimicking dephosphorylation and phosphorylation, respectively. In T lymphocytes, expression of IKZF1 led to T helper (T) differentiation skewed towards T2. Thus, our data indicate that the IKZF1 behaves as a GOF variant underlying immune dysregulation. Disturbed IKZF1 phosphorylation represents a novel GOF mechanism (gain-of-function by loss-of-phosphorylation; GOF-LOP), associated with immune dysregulation, highlighting the regulatory role of IKZF1 during cell cycle progression through phosphorylation.

中文翻译：

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IKZF1 磷酸化缺失导致与免疫失调相关的功能获得

免疫失调通常表现为自身免疫、炎症和/或淋巴细胞增殖。一些种系遗传缺陷与免疫失调有关，包括 杂合功能获得性 (GOF) 突变，这是一种含有锌指结构域 (ZF) 的造血的重要转录因子。然而，在很大一部分患者中，其免疫失调的遗传起源仍未确定。研究人员对一个有两名成员出现免疫失调症状的家庭进行了研究，以确定其疾病的遗传原因。进行了全外显子组测序、免疫学参数分析、功能测定（包括蛋白质印迹、细胞周期期间的 EMSA 和 T 辅助细胞分化）。这两名患者携带一种新型杂合突变（IKZF1）。先前已证明，1 杂合突变通过直接影响 ZF 与 DNA 结合或二聚化的能力，导致几种不同的人类免疫疾病。在此，我们发现 ZF 之外的 IKZF1 导致 IKZF1 磷酸化受损，导致细胞周期 S 期 DNA 结合能力增强、G1-S 期转变减少和增殖减少。证实这些数据的是，在 IKZF1 中观察到了类似的功能改变，但在模拟去磷酸化和磷酸化的 IKZF1 中则没有观察到类似的功能改变。在 T 淋巴细胞中，IKZF1 的表达导致辅助性 T (T) 分化偏向 T2。因此，我们的数据表明 IKZF1 表现为导致免疫失调的 GOF 变体。IKZF1 磷酸化紊乱代表了一种新的 GOF 机制（通过磷酸化丧失获得功能；GOF-LOP），与免疫失调相关，强调了 IKZF1 通过磷酸化在细胞周期进程中的调节作用。