Alt. symbols: MUM1 | LSIRF

Approved name: interferon regulatory factor 4
Alt. names: interferon regulatory factor 4 | lymphocytespecific interferon regulatory factor | multiple myeloma oncogene 1

Location: 6p25.3: 391739 - 411443 (+)
Gene type: protein_coding, 8 transcripts.

Scores: LoFtool: 0.542000 | pLI: 0.03209263 | LOEUF: 0.382

HGNC: 6119

NCBI: 3662, RefSeq: NG_027728.1

Ensembl: ENSG00000137265.16

LRG_ | Status: none

OMIM: 601900

Expression | ProteinAtlas

Interferon regulatory factors (IRFs) are a family of transcription factors (TFs) with essentials role in various aspects of the innate and adaptive immune response, including immune cell development, differentiation, and death, as well as regulation of host responses to diverse stimuli. Interferon regulatory factor 4 (IRF4), also known as MUM1, is composed of a highly conserved N-terminal DNA binding domain (DBD) and a C-terminal IRF association domain (IAD) critical for its interaction with IRFs and other TFs, connected by a flexible linker (PMID: 26405037). The last 30 residues of the IAD also comprise an auto-inhibitory region (AR) that binds to and regulates the DBD's interactions with target DNA. IRF4 is considered unique amongst the IRFs because its expression is restricted to immune cells (B cells, T cells and certain myeloid lineages (dendritic cells and macrophages)), and it is the only IRF whose expression is induced by a range of diverse mitogenic stimuli, including LPS, antigen receptor engagement, IL-4, and CD40 signaling, rather than interferons (PMID: 10601358, 16243976, 20580461, 27826752). Specifically, IRF4 promotes the differentiation of naïve CD4+ T cells into Th2, Th9, Th17, or Tfh effector lineages and is also required for the function of regulatory T cells (Tregs) (PMID: 24782159). IRF4 is also essential for for the differentiation of naïve CD8+ T cells into IL-9-producing (Tc9) and IL-17-producing (Tc17) effector lineages, as well as for CD8+ T-cell memory formation. IRF4 is expressed at various stages of B cell development, including through memory B and plasma cell stages. It is considered one of the key drivers of B cell development because it regulates key processes in B cell differentiation and function including B cell receptor (BCR) signaling, germinal center formation, isotype class switch recombination (PMID: 33024284). Given its many roles, IRF4 dysregulation is also linked to many lymphoid malignancies. Depending on the context and stage of hematopoietic cell differentiation in which its expression is dysregulated, it may act as either an oncogene or a tumor-suppressor.

Garcia-Morato et al. (2018) identified a homozygous IRF4 splice acceptor site mutation (c.1213-2A>G, p.V405GfsTer127) in a 5-month-old daughter of nonconsanguineous parents with combined immunodeficiency (CID) (PMID: 29408330). Her clinical presentation included IUGR, failure to thrive, severe dermatitis, long periods of unexplained fevers, bronchopneumonia, diarrhea, generalized lymphadenopathy, episodes of fasting hypoglycemia and excessive sweating. She died at age 2 after having just receive d allogeneic HSCT. SNP array found a significant loss of heterozygosity across the entirety of chromosome 6, suggesting that her homozygous state arose from maternal UPD. Her mother and grandmother were both found to be heterozygous for the same variant. Guerin et al. (2018) identified a rare non-synonymous heterozygous loss-of-function variant (R98W) in 4 patients with Whipple's disease (WD) (PMID: 29537367). This mutation modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. The authors showed that AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance. The IRF4 Consortium - Fornes et al. (2023) - described a recurrent heterozygous IRF4 DBD mutation (T95R) causing an autosomal dominant CID in 7 patients from 6 unrelated families (PMID: 36662884). The patients presented with susceptibility to opportunistic infections and agammaglobulinemia. This variant altered IRF4's canonical DNA binding specificities and led to multimorphic effects (LOF, GOF, neomorphic). Thouenon et al. (2023) described a heterozygous neomorphic IAD domain variant (c.1075 T>C, p.(F359L)) in 3 patients from a 2-generation family who presented with hypogammaglobulinemia and early onset recurrent bacterial, viral and fungal infections, predominantly sinorespiratory, GI and mucocutaneous, as well as skin and hair depigmentation (PMID: 36917008). [Load More]