#619437
Table of Contents
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
17q12-q21.1 | ?Immunodeficiency 84 | 619437 | AD | 3 | IKZF3 | 606221 |
A number sign (#) is used with this entry because of evidence that immunodeficiency-84 (IMD84) is caused by heterozygous mutation in the IKZF3 gene (606221) on chromosome 17q12-q21. One such family has been reported.
Immunodeficiency-84 (IMD84) is an autosomal dominant primary immunologic disorder characterized by recurrent sinopulmonary infections from childhood associated with low levels of B cells and impaired early B-cell development. There may also be variable T-cell abnormalities. Patients with IMD84 have increased susceptibility to infection with Epstein-Barr virus (EBV) and may develop lymphoma in adulthood (summary by Yamashita et al., 2021).
Yamashita et al. (2021) reported a Japanese family in which a woman and her 2 children had a primary immunodeficiency with decreased B cells and susceptibility to Epstein-Barr virus infection. The patients had recurrent sinopulmonary infections since childhood. The mother had splenomegaly at age 39 years; at age 42, she developed cervical non-Hodgkin lymphoma, which was a mixture of follicular lymphoma and EBV-positive diffuse large B-cell lymphoma. She also had pancytopenia and hypogammaglobulinemia. She underwent a bone marrow transplant, but died of multiple organ failure. Her son had recurrent infections and perianal abscesses since childhood. At age 20, he developed EBV-positive diffuse B-cell lymphoma and underwent successful bone marrow transplant. The daughter had mononucleosis, EBV-associated hemophagocytic syndrome, and chronic active EBV disease leading to fatal gastrointestinal bleeding at age 6. All patients had low circulating B cells. Bone marrow examination of the mother showed low levels of B-cell progenitors. Laboratory studies also showed T-cell abnormalities, such as skewing of CD4+ memory and helper T-cell subsets.
The transmission pattern of IMD84 in the family reported by Yamashita et al. (2021) was consistent with autosomal dominant inheritance.
In a woman and her 2 children with IMD84, Yamashita et al. (2021) identified a heterozygous missense mutation in the DNA-binding domain of the IKZF3 gene (G159R; 606221.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. In vitro functional studies in cells transfected with the mutation indicated that it interfered with DNA binding and had a dominant-negative effect on the wildtype protein. Genomewide DNA-binding ability was altered in B cells expressing the mutation, and the altered IKZF3 protein was able to bind to aberrant DNA sequences. Mutant mice expressing a homozygous or heterozygous G158R mutation, corresponding to the human G159R mutation, had a profound defect in B-cell development that was more severe in homozygous mice. The blockade, which occurred at the pre-pro-B cell to pro-B and pre-B cell stage, was accompanied by notably decreased B-cell levels in the bone marrow and spleen. T-cell abnormalities, such as skewed subsets of CD4+ and CD8+ T cells, were also observed. Mice with homozygous loss of Ikzf3 did not have impaired B-cell development, suggesting that loss of function is not the pathogenic mechanism in this disorder. Transcriptome analysis of cells derived from mutant mice confirmed that the mutant Ikzf3 protein acquired the ability to bind to aberrant sequences and formed heterodimers that interfered with normal localization of Ikzf1 (603023). The B- and T-cell defects observed in mutant mice could be rescued by expression of an Ikzf3 variant that still carried the mutation but lacked the Ikzf1 dimerization domain. The authors concluded that sequestration of Ikaros via heterodimer formation conferred by the G159R mutation is the cause of B- and T-cell abnormalities.
Yamashita, M., Kuehn, H. S., Okuyama, K., Okada, S., Inoue, Y., Mitsuiki, N., Imai, K., Takagi, M., Kanegane, H., Takeuchi, M., Shimojo, N., Tsumura, M., Padhi, A. K., Zhang, K. Y. J., Boisson, B., Casanova, J.-L., Ohara, O., Rosenzweig, S. D., Taniuchi, I., and Morio, T. A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS. Nature Immun. 22: 893-903, 2021. [PubMed: 34155405, related citations] [Full Text]
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
17q12-q21.1 | ?Immunodeficiency 84 | 619437 | Autosomal dominant | 3 | IKZF3 | 606221 |
A number sign (#) is used with this entry because of evidence that immunodeficiency-84 (IMD84) is caused by heterozygous mutation in the IKZF3 gene (606221) on chromosome 17q12-q21. One such family has been reported.
Immunodeficiency-84 (IMD84) is an autosomal dominant primary immunologic disorder characterized by recurrent sinopulmonary infections from childhood associated with low levels of B cells and impaired early B-cell development. There may also be variable T-cell abnormalities. Patients with IMD84 have increased susceptibility to infection with Epstein-Barr virus (EBV) and may develop lymphoma in adulthood (summary by Yamashita et al., 2021).
Yamashita et al. (2021) reported a Japanese family in which a woman and her 2 children had a primary immunodeficiency with decreased B cells and susceptibility to Epstein-Barr virus infection. The patients had recurrent sinopulmonary infections since childhood. The mother had splenomegaly at age 39 years; at age 42, she developed cervical non-Hodgkin lymphoma, which was a mixture of follicular lymphoma and EBV-positive diffuse large B-cell lymphoma. She also had pancytopenia and hypogammaglobulinemia. She underwent a bone marrow transplant, but died of multiple organ failure. Her son had recurrent infections and perianal abscesses since childhood. At age 20, he developed EBV-positive diffuse B-cell lymphoma and underwent successful bone marrow transplant. The daughter had mononucleosis, EBV-associated hemophagocytic syndrome, and chronic active EBV disease leading to fatal gastrointestinal bleeding at age 6. All patients had low circulating B cells. Bone marrow examination of the mother showed low levels of B-cell progenitors. Laboratory studies also showed T-cell abnormalities, such as skewing of CD4+ memory and helper T-cell subsets.
The transmission pattern of IMD84 in the family reported by Yamashita et al. (2021) was consistent with autosomal dominant inheritance.
In a woman and her 2 children with IMD84, Yamashita et al. (2021) identified a heterozygous missense mutation in the DNA-binding domain of the IKZF3 gene (G159R; 606221.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. In vitro functional studies in cells transfected with the mutation indicated that it interfered with DNA binding and had a dominant-negative effect on the wildtype protein. Genomewide DNA-binding ability was altered in B cells expressing the mutation, and the altered IKZF3 protein was able to bind to aberrant DNA sequences. Mutant mice expressing a homozygous or heterozygous G158R mutation, corresponding to the human G159R mutation, had a profound defect in B-cell development that was more severe in homozygous mice. The blockade, which occurred at the pre-pro-B cell to pro-B and pre-B cell stage, was accompanied by notably decreased B-cell levels in the bone marrow and spleen. T-cell abnormalities, such as skewed subsets of CD4+ and CD8+ T cells, were also observed. Mice with homozygous loss of Ikzf3 did not have impaired B-cell development, suggesting that loss of function is not the pathogenic mechanism in this disorder. Transcriptome analysis of cells derived from mutant mice confirmed that the mutant Ikzf3 protein acquired the ability to bind to aberrant sequences and formed heterodimers that interfered with normal localization of Ikzf1 (603023). The B- and T-cell defects observed in mutant mice could be rescued by expression of an Ikzf3 variant that still carried the mutation but lacked the Ikzf1 dimerization domain. The authors concluded that sequestration of Ikaros via heterodimer formation conferred by the G159R mutation is the cause of B- and T-cell abnormalities.
Yamashita, M., Kuehn, H. S., Okuyama, K., Okada, S., Inoue, Y., Mitsuiki, N., Imai, K., Takagi, M., Kanegane, H., Takeuchi, M., Shimojo, N., Tsumura, M., Padhi, A. K., Zhang, K. Y. J., Boisson, B., Casanova, J.-L., Ohara, O., Rosenzweig, S. D., Taniuchi, I., and Morio, T. A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS. Nature Immun. 22: 893-903, 2021. [PubMed: 34155405] [Full Text: https://doi.org/10.1038/s41590-021-00951-z]
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