A Variant in Human AIOLOS Impairs Adaptive Immunity by Interfering with IKAROS

A missense mutation (G158R) in Aiolos, encoded by Ikzf3 gene, resulted in defective generation of B cells in mice. Pre-B cells were profoundly decreased in homozygous mutant mice. Heterozygous mutant mice showed milder B cell developmental defects, and B cells in the secondary lymphoid organs decreased. Genome-wide binding of Aiolos and Ikaros were altered in the thymus of homozygous Ikzf3 G158R mice. Our findings indicate that Aiolos-G158R hinders B cell development by interfering Ikaros' function via formation of heterodimers. A heterozygous missense variant (G159R) in AIOLOS, encoded by IKZF3 gene, resulted in impaired adaptive immunity, which predominantly manifested as profound B cell developmental defect. Genome-wide binding of wild-type AIOLOS and AIOLOS G159R mutant were examined in IKZF3 knock-out human pre-B cell line NALM-6, retrovirally transduced with doxycycline inducible wild-type AIOLOS or AIOLOS G159R. Changes in genome-wide binding and binding motif were observed for AIOLOS G159R mutant. Sample 1-6: mRNA profiles of pre-B cells in wild-type and heterozygous Ikzf3 G158R mutant mice. Sample 7-16: Genome-wide bindings of Ikaros and Aiolos in the thymocytes of wild-type and homozygous Ikzf3 G158R mutant mice. Sample 17-26: Genome-wide bindings of WT AIOLOS and AIOLOS G159R mutant in IKZF3 knockout human pre-B cell line NALM6.