AIOLOS haploinsufficiency is associated with immunodeficiency, autoimmunity, and allergy

Abstract

AIOLOS is a transcription factor of the IKAROS family, that is highly expressed in the lymphoid lineage and plays an important role in lymphocyte differentiation and development. Recently, two heterozygous AIOLOS germline mutations (G159R and N160S) were reported in primary immunodeficiency patients. Both variants associated distinctive and unique T and B cell differentiation defects, hematologic malignancies, and infectious disease susceptibility patterns through different dominant negative (DN) mechanisms. Here we report seven individuals from three unrelated families carrying AIOLOS variants Q402* (nonsense, 1 family) and E82K (missense, 2 families), leading to AIOLOS haploinsufficiency through different mechanisms of action. Clinically, patients with AIOLOS haploinsufficiency showed hypogammaglobulinemia, recurrent respiratory tract infections, and immune dysregulation manifested by autoimmunity and allergy, with incomplete clinical penetrance. Mechanistically, while the nonsense mutant Q402* is devoid of its C-terminal zinc-finger (ZF) dimerization domain (ZF5-6), it is still able to homodimerize with wildtype (WT) AIOLOS although unable to heterodimerize with WT IKAROS or HELIOS. We introduce new insights into AIOLOS biology as we found that AIOLOS ZF1, a part of AIOLOS DNA binding domain (ZF1-4), was associated with noncanonical dimerization and negative regulation of DNA binding. Further studies revealed that the mutant Q402* displayed abnormalities of DNA binding, pericentromeric targeting, post-transcriptional modification, and transcriptome regulation by haploinsufficiency. In contrast, mutant E82K showed overall normal AIOLOS functions; however, by affecting a newly defined AIOLOS protein stability domain, it also led to AIOLOS haploinsufficiency. Unlike the previously reported AIOLOS mutations, heterozygous variants Q402* and E82K do not have a DN effect over other IKAROS family proteins. Our data extend the spectrum of pathogenic variants of AIOLOS-associated diseases and provide a novel mechanism of homodimerization and protein stability that, when disrupted, could affect human health.