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A Point Mutation in IKAROS ZF1 Causes a B Cell Deficiency in Mice


IKZF1 (IKAROS) is essential for normal lymphopoiesis in both humans and mice. Previous Ikzf1 mouse models have demonstrated the dual role for IKZF1 in both B and T cell development and have indicated differential requirements of each zinc finger. Furthermore, mutations in IKZF1 are known to cause common variable immunodeficiency in patients characterized by a loss of B cells and reduced Ab production. Through N-ethyl-N-nitrosourea mutagenesis, we have discovered a novel Ikzf1 mutant mouse with a missense mutation (L132P) in zinc finger 1 (ZF1) located in the DNA binding domain. Unlike other previously reported murine Ikzf1 mutations, this L132P point mutation (Ikzf1(L132P) ) conserves overall protein expression and has a B cell-specific phenotype with no effect on T cell development, indicating that ZF1 is not required for T cells. Mice have reduced Ab responses to immunization and show a progressive loss of serum Igs compared with wild-type littermates. IKZF1(L132P) overexpressed in NIH3T3 or HEK293T cells failed to localize to pericentromeric heterochromatin and bind target DNA sequences. Coexpression of wild-type and mutant IKZF1, however, allows for localization to pericentromeric heterochromatin and binding to DNA indicating a haploinsufficient mechanism of action for IKZF1(L132P) Furthermore, Ikzf1(+/L132P) mice have late onset defective Ig production, similar to what is observed in common variable immunodeficiency patients. RNA sequencing revealed a total loss of Hsf1 expression in follicular B cells, suggesting a possible functional link for the humoral immune response defects observed in Ikzf1(L132P/L132P) mice.

Type Journal
ISBN 1550-6606 (Electronic) 0022-1767 (Linking)
Authors Boast, B.; Miosge, L. A.; Kuehn, H. S.; Cho, V.; Athanasopoulos, V.; McNamara, H. A.; Sontani, Y.; Mei, Y.; Howard, D.; Sutton, H. J.; Omari, S. A.; Yu, Z.; Nasreen, M.; Andrews, T. D.; Cockburn, I. A.; Goodnow, C. C.; Rosenzweig, S. D.; Enders, A.
Responsible Garvan Author Prof Christopher Goodnow
Published Date 2021-04-30
Published Volume 206
Published Issue 7
Published Pages 1505-1514
Status Published in-print
DOI 10.4049/jimmunol.1901464
URL link to publisher's version