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|Mutation Type||splice donor site|
|Coordinate||30,761,490 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||interferon regulatory factor 4|
|Chromosomal Location||30,749,226-30,766,976 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the IRF (interferon regulatory factor) family of transcription factors, characterized by an unique tryptophan pentad repeat DNA-binding domain. The IRFs are important in the regulation of interferons in response to infection by virus, and in the regulation of interferon-inducible genes. This family member is lymphocyte specific and negatively regulates Toll-like-receptor (TLR) signaling that is central to the activation of innate and adaptive immune systems. A chromosomal translocation involving this gene and the IgH locus, t(6;14)(p25;q32), may be a cause of multiple myeloma. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2010]
PHENOTYPE: Mice homozygous for disruptions in this gene display immune system abnormalities involving development of both T and B cells and affecting susceptibility to both bacterial and viral infections as well as impaired thermogenic gene expression and energy expenditure. [provided by MGI curators]
|Limits of the Critical Region||30749226 - 30766927 bp|
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000021784] [ENSMUSP00000105936]|
|Predicted Effect||probably benign|
|Predicted Effect||probably benign|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Last Updated||2017-05-12 11:13 AM by Anne Murray|
|Record Created||2016-01-07 11:06 PM by Jin Huk Choi|
The Honey2 phenotype was identified among G3 mice of the pedigree R3889, some of which showed a diminished T-dependent antibody response (IgG) to recombinant Semliki Forest virus (rSFV)-encoded β-galactosidase (rSFV-β-gal) (Figure 1) and a diminished T-independent antibody (IgM) response to 4-hydroxy-3-nitrophenylacetyl-Ficoll (NP-Ficoll) (Figure 2).
|Nature of Mutation|
The effect of the mutation at the cDNA and protein level has not examined. The mutation is judged unlikely to disrupt the splice donor site of intron 8 by splice prediction programs. In the case that this mutation affects splicing, a cryptic splice site in exon 8 might be used, resulting in a transcript that has a 50-base pair deletion in exon 8 (out of 9 total exons). The mutation would lead to a frame-shifted protein product beginning after amino acid 388 of the protein, followed by premature termination after the inclusion of 26 aberrant amino acids.
Genomic numbering corresponds to NC_000079. The donor splice site of intron 8, which is destroyed by the Honey2 mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
The Irf4 gene encodes one of nine members of the interferon regulatory factor (IRF) family of transcription factors, which regulate the transcription of type I interferons (IFN-α/β) and IFN-inducible genes during immune system development, homeostasis and activation by microbes [reviewed by (1;2)]. As in the other IRFs, the N-terminal half of IRF4 (residues 20-137) serves as the DNA binding region (3), and is characterized by the presence of five highly conserved tryptophans (residues 27, 42, 54, 74 and 93) each separated by 10-18 amino acids (Figure 4) (4). IRF family proteins share sequence and structural homology in their DNA binding regions, and all bind to a similar DNA motif (A/G NGAAANNGAAACT) called the IFN-stimulated response element (ISRE) (5) or IFN regulatory element (6) that is present in the regulatory regions of interferons and interferon-stimulated genes (ISGs). By itself, IRF4 only possesses weak DNA binding affinity (3), but can function as both a transcriptional activator and repressor depending upon the specific promoter and binding partner. The C-terminal halves of all IRF family members contain either an IRF association domain 1 (IAD1) or an IAD2, with which they bind to other IRFs, other transcription factors, or self-associate. These interactions allow the IRFs to modulate their activity and target a variety of genes. The IAD1 is approximately 177 amino acids in length, and is conserved in all IRFs except IRF1 and IRF2. IAD2 domains are found only in IRF1 and IRF2 (7-9). By homology, the mouse IRF4 IAD1 domain occurs at amino acids 245-412 (9), and along with the DBD is necessary for interactions with other IRFs, PU.1 and other transcription factors (10). IRF4 also contains an activation domain located within amino acids 150-450. Two regions within this sequence may serve as the potential activation domain: a proline-rich segment (amino acids 151-237) and a carboxy-terminal region (amino acids 354-419) containing 15% glutamine residues (10). A conserved bipartite nuclear retention signal is located within amino acids 50-100 of the DBD.
The mutation in Honey2 putatively results in the deletion of 50-base pairs from exon 8, subsequently leading to a frame-shift after amino acid 388, and premature termination after the inclusion of 26 aberrant amino acids. Amino acid 388 is within the carboxy-terminal region of the activation domain. The frame-shift and premature termination would also affect the IAD1 domain.
Please see the record for honey for more information about Irf4.
Initially, IRF4-deficient animals displayed normal lymphocyte levels, but developed generalized lymphadenopathy with expansion of both T and B lymphocytes after four to five weeks. These animals also failed to develop germinal centers (GCs) in B cell follicles or plasma cells after immunization, had poor T and B cell proliferative responses after stimulation with most mitogens, and lacked production of all serum Ig subclasses after immunization with T cell-dependent or -independent antigens. Furthermore, these mice were unable to mount an effective anti-viral response to lymphocyticchoriomeningitis virus suggesting severe immunodeficiency. A block at a late stage of peripheral B cell maturation was discovered in these animals. These results suggest that IRF4 is essential for mature B and T cell function. The severe reduction in serum immunoglobulin and lack of GCs observed in IRF4-deficient mice (11) is due to the critical role IRF4 plays in isotype switching and plasma cell differentiation (12;13).
IRF4 appears to be expressed in several types of lymphoid malignancies including T cell leukemias and multiple myeloma (OMIM: #254500). Translocations involving the IRF4 gene occur in a subset of peripheral T cell lymphomas (14), and some cases of multiple myeloma contain a chromosomal translocation that juxtaposes the immunoglobulin heavy-chain locus to the Irf4 gene resulting in IRF overexpression (15). IRF4 mRNA expression is a prognostic marker for poor survival in these patients (16), and IRF4 is required for the survival of multiple myeloma cell lines (17).
The defective antibody production observed in Honey2 mice is consistent with the B cell phenotype observed in Irf4-/- animals. The Irf4-/- mice display a normal distribution of B and T lymphocyes at 4 to 5 weeks of age, but develop progressive generalized lymphadenopathy with an absence of both T-independent and T-dependent antibody responses (11). The similarity of these phenotypes to those seen in Honey2 mice suggests that the Honey2 mutation severely affects the function of IRF4.
Honey2(F):5'- ACCAGGTGTCTGAACAGTTTGG -3'
Honey2(R):5'- TTGGGTCCAAGTCATCTGCC -3'
Honey2_seq(F):5'- GAGATTCCAGGTGACTCT -3'
Honey2_seq(R):5'- ATCTGCCCTGCTGATTCGGTG -3'
1. Tamura, T., Yanai, H., Savitsky, D., and Taniguchi, T. (2008) The IRF Family Transcription Factors in Immunity and Oncogenesis. Annu Rev Immunol. 26, 535-584.
2. Savitsky, D., Tamura, T., Yanai, H., and Taniguchi, T. (2010) Regulation of Immunity and Oncogenesis by the IRF Transcription Factor Family. Cancer Immunol Immunother. 59, 489-510.
3. Yee, A. A., Yin, P., Siderovski, D. P., Mak, T. W., Litchfield, D. W., and Arrowsmith, C. H. (1998) Cooperative Interaction between the DNA-Binding Domains of PU.1 and IRF4. J Mol Biol. 279, 1075-1083.
4. Matsuyama, T., Grossman, A., Mittrucker, H. W., Siderovski, D. P., Kiefer, F., Kawakami, T., Richardson, C. D., Taniguchi, T., Yoshinaga, S. K., and Mak, T. W. (1995) Molecular Cloning of LSIRF, a Lymphoid-Specific Member of the Interferon Regulatory Factor Family that Binds the Interferon-Stimulated Response Element (ISRE). Nucleic Acids Res. 23, 2127-2136.
5. Darnell, J. E.,Jr., Kerr, I. M., and Stark, G. R. (1994) Jak-STAT Pathways and Transcriptional Activation in Response to IFNs and Other Extracellular Signaling Proteins. Science. 264, 1415-1421.
6. Tanaka, N., Kawakami, T., and Taniguchi, T. (1993) Recognition DNA Sequences of Interferon Regulatory Factor 1 (IRF-1) and IRF-2, Regulators of Cell Growth and the Interferon System. Mol Cell Biol. 13, 4531-4538.
7. Sharf, R., Azriel, A., Lejbkowicz, F., Winograd, S. S., Ehrlich, R., and Levi, B. Z. (1995) Functional Domain Analysis of Interferon Consensus Sequence Binding Protein (ICSBP) and its Association with Interferon Regulatory Factors. J Biol Chem. 270, 13063-13069.
8. Sharf, R., Meraro, D., Azriel, A., Thornton, A. M., Ozato, K., Petricoin, E. F., Larner, A. C., Schaper, F., Hauser, H., and Levi, B. Z. (1997) Phosphorylation Events Modulate the Ability of Interferon Consensus Sequence Binding Protein to Interact with Interferon Regulatory Factors and to Bind DNA. J Biol Chem. 272, 9785-9792.
9. Meraro, D., Hashmueli, S., Koren, B., Azriel, A., Oumard, A., Kirchhoff, S., Hauser, H., Nagulapalli, S., Atchison, M. L., and Levi, B. Z. (1999) Protein-Protein and DNA-Protein Interactions Affect the Activity of Lymphoid-Specific IFN Regulatory Factors. J Immunol. 163, 6468-6478.
10. Brass, A. L., Kehrli, E., Eisenbeis, C. F., Storb, U., and Singh, H. (1996) Pip, a Lymphoid-Restricted IRF, Contains a Regulatory Domain that is Important for Autoinhibition and Ternary Complex Formation with the Ets Factor PU.1. Genes Dev. 10, 2335-2347.
11. Mittrucker, H. W., Matsuyama, T., Grossman, A., Kundig, T. M., Potter, J., Shahinian, A., Wakeham, A., Patterson, B., Ohashi, P. S., and Mak, T. W. (1997) Requirement for the Transcription Factor LSIRF/IRF4 for Mature B and T Lymphocyte Function. Science. 275, 540-543.
12. Sciammas, R., Shaffer, A. L., Schatz, J. H., Zhao, H., Staudt, L. M., and Singh, H. (2006) Graded Expression of Interferon Regulatory Factor-4 Coordinates Isotype Switching with Plasma Cell Differentiation. Immunity. 25, 225-236.
13. Klein, U., Casola, S., Cattoretti, G., Shen, Q., Lia, M., Mo, T., Ludwig, T., Rajewsky, K., and Dalla-Favera, R. (2006) Transcription Factor IRF4 Controls Plasma Cell Differentiation and Class-Switch Recombination. Nat Immunol. 7, 773-782.
14. Feldman, A. L., Law, M., Remstein, E. D., Macon, W. R., Erickson, L. A., Grogg, K. L., Kurtin, P. J., and Dogan, A. (2009) Recurrent Translocations Involving the IRF4 Oncogene Locus in Peripheral T-Cell Lymphomas. Leukemia. 23, 574-580.
15. Iida, S., Rao, P. H., Butler, M., Corradini, P., Boccadoro, M., Klein, B., Chaganti, R. S., and Dalla-Favera, R. (1997) Deregulation of MUM1/IRF4 by Chromosomal Translocation in Multiple Myeloma. Nat Genet. 17, 226-230.
16. Heintel, D., Zojer, N., Schreder, M., Strasser-Weippl, K., Kainz, B., Vesely, M., Gisslinger, H., Drach, J., Gaiger, A., Jager, U., and Ludwig, H. (2008) Expression of MUM1/IRF4 mRNA as a Prognostic Marker in Patients with Multiple Myeloma. Leukemia. 22, 441-445.
|Science Writers||Anne Murray|
|Authors||Jin Huk Choi, James Butler, and Bruce Beutler|
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