AIOLOS Variants Causing Immunodeficiency in Human and Mice

Abstract

AIOLOS is encoded by IKZF3 and is a member of the IKAROS zinc finger transcription factor family. Heterozygous missense variants in the second zinc finger of AIOLOS have recently been reported to be found in the families of patients with inborn errors of immunity. The AIOLOS^G159R variant was identified in patients with B-lymphopenia and familial Epstein-Barr virus-associated lymphoma. Early B-cell progenitors were significantly reduced in the bone marrow of patients with AIOLOS^G159R. Another variant, AIOLOS^N160S was identified in the patients presented with hypogammaglobulinemia, susceptibility to Pneumocystis jirovecii pneumonia, and chronic lymphocytic leukemia. Patients with AIOLOS^N160S had mostly normal B cell counts but showed increased levels of CD21^lo B cells, decreased CD23 expression, and abrogated CD40 response. Both variants were determined to be loss-of-function. Mouse models harboring the corresponding patient's variants recapitulated the phenotypes of the patients. AIOLOS is therefore a novel disease-causing gene in human adaptive immune deficiency.

Keywords: AIOLOS; IKAROS; IKZF transcription factor; IKZF3; inborn errors of immunity.

Figure 1

IKZF protein structures. (A) DNA-binding zinc fingers (ZF1–4) and dimerizing zinc fingers (ZF5–6) are represented by light green and yellow boxes, respectively. The colored lines represent the germline variants reported in IEIs (IKAROS, HELIOS, and AIOLOS) and hereditary thrombocytopenia (PEGASUS). The exon junctions are indicated with dashed lines. (B) Amino acid sequences of the ZF2 of IKAROS and AIOLOS are presented. The numbers indicate the positions of amino acids, whereas red letters represent the amino acids interacting with zinc ions. Above, the secondary structures of ZF2 are shown with the numbers represent amino acid positions in reference to the beginning of α helix. Missense variants of amino acids with purple background are known to be the causes of IKAROS deficiency. Missense variants of G159 (light green background) and N160 (pink background) are known to cause immunodeficiency. The arginine substitution of L162 (yellow background) is known as the hotspot somatic mutation in CLL.

Figure 2

Summary of patients, murine models, and in vitro studies of AIOLOS variants. Circles indicate the patients who presented with the indicated phenotypes. Each column of the circle represents each patient, sorted by the age of the patients. Pedigrees of the study patients are presented above. Two patients with AIOLOS^G159R had died at the time of the study. The phenotypes of both heterozygous (Het) and homozygous (Homo) mice were presented. EBV, Epstein–Barr virus; CLL, chronic lymphocytic leukemia; FO, follicular; MZ, marginal zone; TCR, T-cell receptor; EMSA, electrophoretic mobility shift assay; DN, dominant-negative; PC-HC, pericentromeric heterochromatin foci formation assay; LOF, loss-of-function.