Alternative titles; symbols
HGNC Approved Gene Symbol: IFRD1
Cytogenetic location: 7q31.1 Genomic coordinates (GRCh38) : 7:112,423,174-112,477,203 (from NCBI)
IFRD1 is a histone deacetylase-dependent transcriptional coregulator expressed during terminal neutrophil differentiation with roles in the regulation of neutrophil effector function and the nerve growth factor (NGF; 162030) pathway (Gu et al., 2009; Brkanac et al., 2009).
By differential screening for cDNAs upregulated during nerve growth factor (NGF; 162030)-induced neural differentiation in rat PC12 cells, Tirone and Shooter (1989) cloned Pc4. The deduced protein contains 3 highly hydrophobic regions. Northern blot analysis of adult rat tissues detected expression in skeletal muscle, heart, and spleen, but not in kidney, liver, and brain. In day-13.5 rat embryonic tissues, expression was detected in brain, placenta, and amnion.
The rat Pc4 gene, initially isolated as a nerve growth factor-inducible sequence in PC12 cells, is necessary for muscle differentiation and may have a role in signal transduction. By searching EST databases with a rat Pc4 cDNA, Buanne et al. (1998) isolated ESTs encoding IFDR1, a human homolog of rat Pc4. The deduced 453-amino acid human IFRD1 protein is 90% identical to both rat and mouse Ifrd1 (Pc4), and 47.6% identical to human SKMc15 (IFRD2; 602725). The C terminus of IFRD1 shows 47.5% similarity to the entire human interferon-gamma (IFNG; 147570) protein. IFRD1 has a calculated molecular mass of 50,685 Da. Northern blot analysis detected a 2.2-kb IFRD1 transcript in several human tissues, although at different levels of expression. At midgestation during mouse development, Ifrd1 was expressed primarily in specific differentiating structures and body organs.
By RT-PCR-based differential display, Vietor et al. (2002) identified Tis7 as a gene upregulated upon Jun (165160)-induced loss of polarity in a mouse mammary epithelial cell line. In unpolarized cells, the level of Tis7 protein was elevated and Tis7 translocated into the nucleus. cDNA microarray analysis revealed that overexpression of Tis7 repressed several genes. By yeast 2-hybrid and coimmunoprecipitation analyses, Vietor et al. (2002) determined that Tis7 interacts with several proteins of the SIN3 complex, including Sin3b (607777), Hdac1 (601241), Ncor (600849), and Sap30 (603378). The coprecipitated complex was enzymatically active and repressed transcription of a reporter gene.
Brkanac et al. (2009) stated that the IFRD1 gene comprises 12 exons.
Based on STSs, Buanne et al. (1998) tentatively mapped the IFRD1 gene to 7q22-q31.
To identify genetic modifiers of lung disease severity in cystic fibrosis (219700), Gu et al. (2009) performed a genomewide single-nucleotide polymorphism (SNP) scan in 1 cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone deacetylase-dependent transcriptional coregulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-null mice showed blunted effector function, associated with decreased NF-kappa-B p65 (RELA; 164014) transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease--a phenotype primarily dependent on hematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. The IFRD SNP rs7817 showed significant association with both cross-sectional or longitudinal measures of lung function with a P value of less than 0.05 after Bonferroni correction. Notably, both family-based association and quantitative transmission disequilibrium tests showed that the heterozygote genotype CT was associated with lower lung function than either homozygote CC or TT.
Brkanac et al. (2009) identified a missense mutation in the IFRD1 gene, a A-to-G transition at nucleotide 743 that resulting in an ile-to-val substitution at codon 172 (I172V), that segregated absolutely with the SMNA (607458) phenotype in a 6-generation American family of Irish descent. Isoleucine-172 is highly conserved across species, but valine at this position is present in elephant, chicken, Xenopus tropicalis, and zebrafish. Brkanac et al. (2009) suggested that this change might affect protein structure. However, they concluded that mutation analysis of IFRD1 in additional patients with similar phenotypes was needed for demonstration of causality and further evaluation of the importance of IFRD1 in neurologic diseases.
Vadivelu et al. (2004) found that Tis7 knockout mice were fertile and showed no gross histologic abnormalities. However, Tis7 disruption delayed skeletal muscle regeneration and altered skeletal muscle isometric contractile properties after muscle crush damage, and it downregulated expression of several muscle-specific genes. Cultured primary myogenic satellite cells from Tis7 -/- mice showed reduced differentiation potential and fusion index. Vadivelu et al. (2004) concluded that TIS7 plays a regulatory role during adult muscle regeneration.
Brkanac, Z., Spencer, D., Shendure, J., Robertson, P. D., Matsushita, M., Vu, T., Bird, T. D., Olson, M. V., Raskind, W. H. IFRD1 is a candidate gene for SMNA on chromosome 7q22-q23. Am. J. Hum. Genet. 84: 692-697, 2009. [PubMed: 19409521] [Full Text: https://doi.org/10.1016/j.ajhg.2009.04.008]
Buanne, P., Incerti, B., Guardavaccaro, D., Avvantaggiato, V., Simeone, A., Tirone, F. Cloning of the human interferon-related developmental regulator (IFRD1) gene coding for the PC4 protein, a member of a novel family of developmentally regulated genes. Genomics 51: 233-242, 1998. [PubMed: 9722946] [Full Text: https://doi.org/10.1006/geno.1998.5260]
Gu, Y., Harley, I. T. W., Henderson, L. B., Aronow, B. J., Vietor, I., Huber, L. A., Harley, J. B., Kilpatrick, J. R., Langefeld, C. D., Williams, A. H., Jegga, A. G., Chen, J., and 11 others. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature 458: 1039-1042, 2009. [PubMed: 19242412] [Full Text: https://doi.org/10.1038/nature07811]
Tirone, F., Shooter, E. M. Early gene regulation by nerve growth factor in PC12 cells: induction of an interferon-related gene. Proc. Nat. Acad. Sci. 86: 2088-2092, 1989. [PubMed: 2467301] [Full Text: https://doi.org/10.1073/pnas.86.6.2088]
Vadivelu, S. K., Kurzbauer, R., Dieplinger, B., Zweyer, M., Schafer, R., Wernig, A., Vietor, I., Huber, L. A. Muscle regeneration and myogenic differentiation defects in mice lacking TIS7. Molec. Cell. Biol. 24: 3514-3525, 2004. Note: Erratum: Molec. Cell. Biol. 25: 11194 only, 2005. [PubMed: 15060170] [Full Text: https://doi.org/10.1128/MCB.24.8.3514-3525.2004]
Vietor, I., Vadivelu, S. K., Wick, N., Hoffman, R., Cotten, M., Seiser, C., Fialka, I., Wunderlich, W., Haase, A., Korinkova, G., Brosch, G., Huber, L. A. TIS7 interacts with the mammalian SIN3 histone deacetylase complex in epithelial cells. EMBO J. 21: 4621-4631, 2002. [PubMed: 12198164] [Full Text: https://doi.org/10.1093/emboj/cdf461]