Alternative titles; symbols
HGNC Approved Gene Symbol: ESRRG
Cytogenetic location: 1q41 Genomic coordinates (GRCh38): 1:216,503,246-217,137,702 (from NCBI)
Members of the nuclear receptor superfamily are important regulators of development, cell proliferation, and physiology. During an analysis of the critical region of type IIa Usher syndrome (USH2A; 276901) at 1q41, Eudy et al. (1998) constructed a cDNA contig of ESRRG. Northern blot analysis detected a 5.5-kb ESRRG transcript in a variety of human adult and fetal tissues, with the highest level in fetal brain. The predicted 436-amino acid ESRRG protein, which is a member of the steroid/thyroid/retinoid receptor superfamily, is 76% identical to the orphan receptor ESRRB (602167) and 63% identical to ESRRA (601998).
Heard et al. (2000) reported that the ESRRG mRNA is highly alternatively spliced at the 5-prime end, giving rise to a number of tissue-specific RNA species, some of which encode protein isoforms differing in the N-terminal region. Like ESRRA and ESRRB, ESRRG binds as a monomer to an ERR-alpha response element (ERRE).
Hong et al. (1999) identified mouse Esrrg, which they called Err3, by yeast 2-hybrid screening using the transcriptional coactivator GRIP1 (604597) as bait. The putative full-length mouse Err3 contains 458 amino acids and is closely related to Err1 and Err2. All ERR family members share an almost identical DNA-binding domain, which shares 68% amino acid identity with that of estrogen receptor. Expression of Err3 in adult mouse was restricted; highest expression was observed in heart, kidney, and brain. In mouse embryo, no expression was observed at day 7, and highest expression occurred around days 11 to 15. Although Err3 is more closely related to Err2 than to Err1, the expression pattern for Err3 was similar to that of Err1 and distinct from that for Err2, suggesting a unique role for Err3 in development.
Using immunohistochemical analysis, Berry et al. (2011) found dynamic Esrrg expression in developing mouse embryo. Earliest Esrrg expression was detected at 9.5 days postcoitus (dpc) in heart and in a subpopulation of head mesenchyme. From 11.5 dpc, Esrrg was expressed in several tubular/ductal structures, including Wolffian duct and urogenital sinus, lung bud, and duodenum, with weaker expression in hepatic ducts. From 18.5 dpc to postnatal day 0, expression was present in renal papilla and in ureteric smooth muscle.
By Southern blot and PCR analyses, Eudy et al. (1998) determined that the ESRRG gene spans approximately 100 kb centered on the microsatellite marker AFM144XF2 in 1q41.
Eudy et al. (1998) mapped the ESRRG gene to the USH2A critical region on chromosome 1q41.
Hong et al. (1999) found that mouse Err3 bound specifically to an estrogen response element and activated reporter genes controlled by estrogen response elements, both in yeast and in mammalian cells, in the absence of any added ligand. A conserved AF2 activation domain located in the hormone-binding domain of Err3 was primarily responsible for transcriptional activation. The Err3 AF2 domain bound GRIP1 in a ligand-independent manner both in vitro and in vivo, through the LxxLL motifs of GRIP1, and GRIP1 functioned as a transcriptional coactivator for Err3 in both yeast and mammalian cells.
Using yeast 2-hybrid analysis and protein pull-down assays, Hentschke and Borgmeyer (2003) showed that human PNRC2 (611882) and TLE1 (600189) interacted with the N-terminal region of mouse Esrrg isoform-2 (ESRRG2). Coexpression of either PNRC2 or TLE1 with Esrrg2 in simian kidney cells resulted in increased reporter gene activity compared with that shown by Esrrg2 alone. Mutation analysis showed that the AF1 domain of Esrrg2 was required for PNRC2-dependent transactivation, whereas both AF1 and AF2 were involved in TLE1-dependent transactivation.
Using explanted embryonic mouse kidney, Berry et al. (2011) found that knockdown of Esrrg caused growth arrest and reduction in the number of nephrons and bud tips. Exposure of explants to an Esrrg agonist also resulted in reduced size and abnormal ductal morphogenesis.
By chromatin immunoprecipitation and genomic DNA analysis of adult mouse heart, Dufour et al. (2007) found that Err-alpha and Err-gamma act as nonobligatory heterodimers to target a common set of promoters involved in the uptake of energy substrates, production and transport of ATP across mitochondrial membranes, and intracellular fuel sensing, as well as calcium handling and contractile work.
By genomic analysis, Alaynick et al. (2007) found that Esrrg regulates a network of nuclear-encoded mitochondrial genes controlling oxidative metabolic function.
Greschik et al. (2002) studied the crystal structure of the ligand-binding domain (LBD) of ERR3 complexed with a steroid receptor coactivator-1 (SRC1; 602691) peptide. The structure revealed a transcriptionally active conformation in absence of any ligand and explained why estradiol does not bind ERRs with significant affinity. Docking of the ERR antagonists diethylstilbestrol and 4-hydroxytamoxifen required structural rearrangements enlarging the ligand-binding pocket that could only be accommodated with an antagonist LBD conformation. Mutant receptors in which the ligand-binding cavity was filled up by bulkier side chains still interacted with SRC1 in vitro and were transcriptionally active in vivo, but were no longer efficiently inactivated by diethylstilbestrol or 4-hydroxytamoxifen. These results provided structural and functional evidence for ligand-independent transcriptional activation by ERR3.
In an infant with congenital sensorineural hearing loss, Schilit et al. (2016) identified a balanced de novo chromosomal translocation, 46,XX,t(1;5)(q32;q15)dn, that disrupted the ESRRG gene on chromosome 1q32 and the KIAA0825 gene (617266) on chromosome 5q15. Due to expression of ESRRG, but not KIAA0825, in inner ear hair cells, disruption of the ESRRG gene was predicted to be causal for hearing loss.
Eudy et al. (1998) did not identify mutations in the ESRRG genes of USH2A patients, and they stated that it was highly unlikely that ESRRG is the USH2A gene.
Alaynick et al. (2007) found that Esrrg -/- mice were born at the expected mendelian ratio and were grossly indistinguishable from wildtype littermates. However, Esrrg -/- mice died perinatally due to abnormal heart and spinal cord function. Embryonic Esrrg -/- hearts showed altered electrocardiograms, metabolic gene expression, and mitochondrial function, in addition to elevated mitochondrial DNA copy number, and failure to switch to an oxidative gene program during the perinatal period.
By genomic analysis of perinatal Errg -/- renal, gastric, and cardiac mouse tissues, Alaynick et al. (2010) found characteristic dysregulation of genes involved in transport processes. In addition, they found altered expression of several genes associated with hypertension.
Berry et al. (2011) found that at 14.5 dpc, Esrrg -/- kidneys were indistinguishable from wildtype, but by 17 dpc, they showed flattened papilla, increased luminal volume, and distorted medullary architecture. Knockdown of Esrrg in mouse cultured embryonic kidneys by siRNA and a small-molecule agonist resulted in severe abnormality of early branching events of the ureteric duct. The authors concluded that Esrrg is required for early branching events of the ureteric duct that occur prior to the onset of nephrogenesis.
Pei et al. (2015) found that neurons of Errg -/- mice exhibited decreased metabolic capacity. Targeted deletion of Errg in hippocampal neurons resulted in grossly normal young that were obtained in the expected mendelian ratio. Mice with Errg knockout in hippocampus were normal in a number of measures, but showed defects in spatial learning and memory. Errg-knockout hippocampal neurons appeared macroscopically normal and exhibited normal baseline electrophysiologic properties. However, they showed impaired long-term potentiation, which was rescued by supplementation with pyruvate, a mitochondrial oxidative phosphorylation substrate.
Alaynick, W. A., Kondo, R. P., Xie, W., He, W., Dufour, C. R., Downes, M., Jonker, J. W., Giles, W., Naviaux, R. K., Giguere, V., Evans, R. M. ERR-gamma directs and maintains the transition to oxidative metabolism in the postnatal heart. Cell Metab. 6: 13-24, 2007. [PubMed: 17618853] [Full Text: https://doi.org/10.1016/j.cmet.2007.06.007]
Alaynick, W. A., Way, J. M., Wilson, S. A., Benson, W. G., Pei, L., Downes, M., Yu, R., Jonker, J. W., Holt, J. A., Rajpal, D. K., Li, H., Stuart, J., McPherson, R., Remlinger, K. S., Chang, C.-Y., McDonnell, D. P., Evans, R. M., Billin, A. N. ERR-gamma regulates cardiac, gastric, and renal potassium homeostasis. Molec. Endocr. 24: 299-309, 2010. [PubMed: 19965931] [Full Text: https://doi.org/10.1210/me.2009-0114]
Berry, R., Harewood, L., Pei, L., Fisher, M., Brownstein, D., Ross, A., Alaynick, W. A., Moss, J., Hastie, N. D., Hohenstein, P., Davies, J. A., Evans, R. M., FitzPatrick, D. R. Esrrg functions in early branch generation of the ureteric bud and is essential for normal development of the renal papilla. Hum. Molec. Genet. 20: 917-926, 2011. [PubMed: 21138943] [Full Text: https://doi.org/10.1093/hmg/ddq530]
Dufour, C. R., Wilson, B. J., Huss, J. M., Kelly, D. P., Alaynick, W. A., Downes, M., Evans, R. M., Blanchette, M., Giguere, V. Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERR-alpha and gamma. Cell Metab. 5: 345-356, 2007. [PubMed: 17488637] [Full Text: https://doi.org/10.1016/j.cmet.2007.03.007]
Eudy, J. D., Yao, S., Weston, M. D., Ma-Edmonds, M., Talmadge, C. B., Cheng, J. J., Kimberling, W. J., Sumegi, J. Isolation of a gene encoding a novel member of the nuclear receptor superfamily from the critical region of Usher syndrome type IIa at 1q41. Genomics 50: 382-384, 1998. [PubMed: 9676434] [Full Text: https://doi.org/10.1006/geno.1998.5345]
Greschik, H., Wurtz, J.-M., Sanglier, S., Bourguet, W., van Dorsselaer, A., Moras, D., Renaud, J.-P. Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Molec. Cell 9: 303-313, 2002. [PubMed: 11864604] [Full Text: https://doi.org/10.1016/s1097-2765(02)00444-6]
Heard, D. J., Norby, P. L., Holloway, J., Vissing, H. Human ERR-gamma, a third member of the estrogen receptor-related receptor (ERR) subfamily of orphan nuclear receptors: tissue-specific isoforms are expressed during development in the adult. Molec. Endocr. 14: 382-392, 2000. [PubMed: 10707956] [Full Text: https://doi.org/10.1210/mend.14.3.0431]
Hentschke, M., Borgmeyer, U. Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERR-gamma. Biochem. Biophys. Res. Commun. 312: 975-982, 2003. [PubMed: 14651967] [Full Text: https://doi.org/10.1016/j.bbrc.2003.11.025]
Hong, H., Yang, L., Stallcup, M. R. Hormone-independent transcriptional activation and coactivator binding by novel orphan nuclear receptor ERR3. J. Biol. Chem. 274: 22618-22626, 1999. [PubMed: 10428842] [Full Text: https://doi.org/10.1074/jbc.274.32.22618]
Pei, L., Mu, Y., Leblanc, M., Alaynick, W., Barish, G. D., Pankratz, M., Tseng, T. W., Kaufman, S., Liddle, C., Yu, R. T., Downes, M., Pfaff, S. L., Auwerx, J., Gage, F. H., Evans, R. M. Dependence of hippocampal function on ERR-gamma-regulated mitochondrial metabolism. Cell Metab. 21: 628-636, 2015. [PubMed: 25863252] [Full Text: https://doi.org/10.1016/j.cmet.2015.03.004]
Schilit, S. L. P., Currall, B. B., Yao, R., Hanscom, C., Collins, R. L., Pillalamarri, V., Lee, D.-Y., Kammin, T., Zepeda-Mendoza, C. J., Mononen, T., Nolan, L. S., Gusella, J. F., Talkowski, M. E., Shen, J., Morton, C. C. Estrogen-related receptor gamma implicated in a phenotype including hearing loss and mild developmental delay. Europ. J. Hum. Genet. 24: 1622-1626, 2016. [PubMed: 27381092] [Full Text: https://doi.org/10.1038/ejhg.2016.64]