| First Author | Boast B | Year | 2021 |
| Journal | J Immunol | Volume | 206 |
| Issue | 7 | Pages | 1505-1514 |
| PubMed ID | 33658297 | Mgi Jnum | J:303895 |
| Mgi Id | MGI:6515408 | Doi | 10.4049/jimmunol.1901464 |
| Citation | Boast B, et al. (2021) A Point Mutation in IKAROS ZF1 Causes a B Cell Deficiency in Mice. J Immunol 206(7):1505-1514 |
| abstractText | 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. |
