Alternative titles; symbols
HGNC Approved Gene Symbol: NRIP1
Cytogenetic location: 21q11.2-q21.1 Genomic coordinates (GRCh38): 21:14,961,235-15,065,936 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q11.2-q21.1 | ?Congenital anomalies of kidney and urinary tract 3 | 618270 | Autosomal dominant | 3 |
The NRIP1 gene encodes a nuclear receptor transcriptional coregulator that plays an integral role in fine-tuning the activity of a large number of transcription factors during development. NRIP1 tends to inhibit transcriptional activity (summary by Vivante et al., 2017).
Cavailles et al. (1995) identified receptor-interacting protein-140 (RIP140) by virtue of its direct association with a transcriptional activation domain of estrogen receptor (ESR; 133430) in the presence of estrogen.
Using the ligand-binding domain of Tr2 (NR2C1; 601529) as bait in a yeast 2-hybrid screen of an embryonic mouse cDNA library, Lee et al. (1998) cloned Rip140. Like the 1,158-amino acid human protein, the deduced mouse protein contains 9 LxxLL signature motifs. Northern blot analysis detected an 8-kb Rip140 transcript in all adult mouse tissues examined and in embryonic day-12.5 placenta and embryos.
Vivante et al. (2017) found expression of the Nrip1 gene in the urogenital system of the developing mouse. Nrip1 transcripts were found in the nephric duct, ureter, and kidney between E11.5 and E18.5. Retinoic acid (RA) increased Nrip1 expression in these tissues. Nrip1 was also expressed in Xenopus during development, particularly in the pronephric tubules.
L'Horset et al. (1996) identified 2 binding sites in RIP140 that interacted with the ligand-binding domain of ESR both in solution and when the receptor was bound to DNA. Both sites independently interacted with other nuclear receptors, including thyroid hormone receptors (e.g., THRB; 190160) and retinoic acid receptors (e.g., RARB; 180220), but their binding properties were not identical. These interactions were enhanced by receptor agonists, but not by antagonists, and in vitro binding of RIP140 to a number of mutant receptors correlated with their ability to stimulate transcription in vivo. When RIP140 was fused to heterologous DNA-binding domains, it could stimulate transcription of reporter genes in both yeast and mammalian cells. L'Horset et al. (1996) concluded that RIP140 functions as a bridge between receptors and the basal transcription machinery and thereby stimulates transcription of target genes.
By mutation analysis, Lee et al. (1998) determined that the LxxLL motifs of mouse Rip140 interacted with the activation function-2 region of Tr2. Coimmunoprecipitation experiments detected interaction between the 2 proteins in cell extracts. Rip140 repressed binding of Tr2 to target DNA and suppressed induction of retinoic acid (RA) receptor (see 180240) by RA in a dose-dependent manner. In the presence of Rip140, Tr2 translocated into the nucleus.
Using yeast 2-hybrid analysis, protein pull-down assays, and coimmunoprecipitation analysis, Sugawara et al. (2001) showed that RIP140 interacted with SF1 (NR5A1; 184757) and DAX1 (NR0B1; 300473), which control expression of STAR (600617), a regulator of intramitochondrial cholesterol transport. Using reporter gene constructs, they showed that RIP140 inhibited STAR expression in an SF1-dependent manner. RIP140 and DAX1 inhibited cAMP-stimulated activity of an SF1 response element synergistically.
White et al. (2008) reviewed the fundamental role of RIP140 in normal cellular function, as well as in pathology of metabolic diseases. They stated that RIP140 can act as a transcriptional repressor or activator depending upon the transcriptional factors with which it interacts. The repressive function of RIP140 can be modulated posttranslationally by phosphorylation, arginine methylation, acetylation, and conjugation of lys613 with pyridoxal 5-prime-phosphate.
By fluorescence in situ hybridization, Cavailles et al. (1995) mapped the RIP140 gene to chromosome 21q11. Katsanis et al. (1998) used hybrids, YACs, and PACs to place the RIP140 gene on the physical map of chromosome 21; 21q11 is a gene-poor region.
In 7 affected members of a 3-generation Yemenite Jewish family (family H) with congenital anomalies of the kidney and urinary tract-3 (CAKUT3; 618270), Vivante et al. (2017) identified a heterozygous 1-bp deletion in the NRIP1 gene (c.279delG; 602490.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, although there was 1 possible unaffected mutation carrier, suggesting incomplete penetrance. In vitro functional expression studies in HEK293 cells showed that the mutant protein remained localized in the cytoplasm, did not translocate to the nucleus, abrogated the NRIP1-RAR interaction, and had no repressor activity for RA-mediated transcription. Coexpression with wildtype NRIP1 showed that the mutation resulted in haploinsufficiency with a loss of function and did not show a dominant-negative effect. Nrip1 was expressed in Xenopus during development, particularly in the pronephric tubules. Morpholino knockdown of the nrip1 gene resulted in distorted pronephric structures, and the mutant mRNA could not rescue the defect.
White et al. (2000) found that Rip140-null mice were viable but smaller than their wildtype littermates. Female mice were completely infertile due to complete failure of mature follicles to release oocytes at ovulation. In contrast, luteinization proceeded normally in Rip140-null mice, resulting in a phenotype similar to luteinized unruptured follicle syndrome in women.
Leonardsson et al. (2004) found that Rip140 -/- mice were lean, resisted high-fat diet-induced obesity and hepatic steatosis, and had increased oxygen consumption. Although adipogenesis was unaffected, expression of certain lipogenic enzymes was reduced. In contrast, genes involved in energy dissipation and mitochondrial uncoupling, including uncoupling protein-1 (UCP1; 113730), were markedly increased. Leonardsson et al. (2004) concluded that RIP140 regulates the expression of genes involved in energy homeostasis.
Vivante et al. (2017) found that heterozygous Nrip1-null mouse embryos had urinary tract abnormalities, including dysplastic kidneys with cystic dilations and severe hydroureter with hydronephrosis and ureterocele.
In 7 affected members of a 3-generation Yemenite Jewish family (family H) with congenital anomalies of the kidney and urinary tract-3 (CAKUT3; 618270), Vivante et al. (2017) identified a heterozygous 1-bp deletion (c.279delG, NM_003489.3) in the NRIP1 gene, resulting in a frameshift and premature termination (Trp93fsTer). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, although there was 1 possible unaffected mutation carrier, suggesting incomplete penetrance. The variant was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutation resulted in a loss of function and was unable to repress RA-mediated transcriptional activity.
Cavailles, V., Dauvois, S., Horset, L. F., Lopez, G., Hoare, S., Kushner, P. J., Parker, M. G. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 14: 3741-3751, 1995. [PubMed: 7641693] [Full Text: https://doi.org/10.1002/j.1460-2075.1995.tb00044.x]
Katsanis, N., Ives, J. H., Groet, J., Nizetic, D., Fisher, E. M. C. Localisation of receptor interacting protein 140 (RIP140) within 100 kb of D21S13 on 21q11, a gene-poor region of the human genome. Hum. Genet. 102: 221-223, 1998. [PubMed: 9521594] [Full Text: https://doi.org/10.1007/s004390050682]
L'Horset, F., Dauvois, S., Heery, D. M., Cavailles, V., Parker, M. G. RIP-140 interacts with multiple nuclear receptors by means of two distinct sites. Molec. Cell. Biol. 16: 6029-6036, 1996. [PubMed: 8887632] [Full Text: https://doi.org/10.1128/MCB.16.11.6029]
Lee, C.-H., Chinpaisal, C., Wei, L.-N. Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2. Molec. Cell. Biol. 18: 6745-6755, 1998. [PubMed: 9774688] [Full Text: https://doi.org/10.1128/MCB.18.11.6745]
Leonardsson, G., Steel, J. H., Christian, M., Pocock, V., Milligan, S., Bell, J., So, P.-W., Medina-Gomez, G., Vidal-Puig, A., White, R., Parker, M. G. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc. Nat. Acad. Sci. 101: 8437-8442, 2004. [PubMed: 15155905] [Full Text: https://doi.org/10.1073/pnas.0401013101]
Sugawara, T., Abe, S., Sakuragi, N., Fujimoto, Y., Nomura, E., Fujieda, K., Saito, M., Fujimoto, S. RIP 140 modulates transcription of the steroidogenic acute regulatory protein gene through interactions with both SF-1 and DAX-1. Endocrinology 142: 3570-3577, 2001. [PubMed: 11459805] [Full Text: https://doi.org/10.1210/endo.142.8.8309]
Vivante, A., Mann, N., Yonath, H., Weiss, A.-C., Getwan, M., Kaminski, M. M., Bohnenpoll, T., Teyssier, C., Chen, J., Shril, S., van der Ven, A. T., Ityel, H., and 18 others. A dominant mutation in nuclear receptor interacting protein 1 causes urinary tract malformations via dysregulation of retinoic acid signaling. J. Am. Soc. Nephrol. 28: 2364-2376, 2017. [PubMed: 28381549] [Full Text: https://doi.org/10.1681/ASN.2016060694]
White, R., Leonardsson, G., Rosewell, I., Jacobs, M. A., Milligan, S., Parker, M. The nuclear receptor co-repressor Nrip1 (RIP140) is essential for female fertility. Nature Med. 6: 1368-1374, 2000. [PubMed: 11100122] [Full Text: https://doi.org/10.1038/82183]
White, R., Morganstein, D., Christian, M., Seth, A., Herzog, B., Parker, M. G. Role of RIP140 in metabolic tissues: connections to disease. FEBS Lett. 582: 39-45, 2008. [PubMed: 18023280] [Full Text: https://doi.org/10.1016/j.febslet.2007.11.017]