Loss-of-phosphorylation of IKZF1 results in gain-of-function associated with immune dysregulation.

BACKGROUNDImmune dysregulation often presents as autoimmunity, inflammation, and/or lymphoproliferation. Several germline genetic defects have been associated with immune dysregulation; they include heterozygous gain-of-function (GOF) mutations in IKZF1, an essential transcription factor for hematopoiesis containing zinc finger domains (ZFs). However, in a large percentage of patients, the genetic origin of their immunedysregulation remains undetermined.OBJECTIVEA family with 2 members presenting immune dysregulation signs was studied to identify the genetic cause of their disease.METHODSWhole exome sequencing, analysis of immunologic parameters, and functional assays (including Western blotting, electrophoretic mobility shift assay during the cell cycle, and T cell differentiation) were performed.RESULTSThe 2 patients carried a novel heterozygous mutation in IKZF1 (IKZF1). IKZF1 heterozygous mutations have previously been shown to be responsible for several distinct human immunologic diseases by directly affecting 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 the 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 cell differentiation skewed toward T2 cells. Thus, our data indicate that IKZF1 behaves as a GOF variant underlying immune dysregulation.CONCLUSIONDisturbed IKZF1 phosphorylation represents a novel GOF mechanism (GOF by loss of phosphorylation (termed as GOF-LOP) associated with immune dysregulation, highlighting the regulatory role of IKZF1 during cell cycle progression through phosphorylation.KEYWORDSIKAROS, IKZF1, Immune dysregulation, T(H)2 cell differentiation, gain-of-function, genetic, inborn errors of immunity, mutation, phosphorylationCopyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.