In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS–IKAROS heterodimers did not bind the canonical AIOLOS–IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner.

在本研究中，我们报告了一种人类遗传性、受损的适应性免疫疾病，主要表现为 B 细胞分化缺陷，由杂合子IKZF3引起错义变体，导致编码的 AIOLOS 蛋白的 DNA 结合域内发生甘氨酸到精氨酸的置换。使用携带相应变体并概括 B 和 T 细胞表型的小鼠，我们表明突变的 AIOLOS 同二聚体和 AIOLOS-IKAROS 异二聚体不结合典型的 AIOLOS-IKAROS DNA 序列。此外，含有一个突变体 AIOLOS 的同源二聚体和异源二聚体与缺乏两个典型基序的基因组区域结合。然而，从突变体 AIOLOS 中去除二聚化能力可以恢复 B 细胞的发育。因此，自适应免疫缺陷是由 AIOLOS 变体劫持 IKAROS 功能引起的。异二聚体干扰是常染色体显性遗传的一种新机制，它通过异二聚体伴侣的突变损害蛋白质功能，从而导致先天性免疫错误。