Alternative titles; symbols
HGNC Approved Gene Symbol: NR0B2
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38) : 1:26,911,489-26,913,975 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.11 | Obesity, mild, early-onset | 601665 | Autosomal dominant; Autosomal recessive; Multifactorial | 3 |
The nuclear receptor superfamily is a group of transcription factors regulated by small hydrophobic hormones, such as retinoic acid, thyroid hormone, and steroids. NR0B2 is an orphan member of the nuclear receptor superfamily that contains the dimerization and ligand-binding domains found in other family members, but lacks the conserved DNA-binding domain. NR0B2 heterodimerizes with other nuclear receptor superfamily members and inhibits transactivation by these receptors (Seol et al., 1996).
Using a yeast 2-hybrid system with a mouse relative of human MB67 (NR1I3; 603881) as the bait, Seol et al. (1996) cloned mouse liver cDNAs encoding Nr0b2, which they named Shp for 'small heterodimer partner.' By screening a human liver cDNA library with a mouse Nr0b2 cDNA, they isolated a human NR0B2 cDNA. Northern blot analysis of human tissues detected an approximately 1.3-kb NR0B2 transcript in liver; lower levels of expression were detected in heart and pancreas. The predicted 257-amino acid NR0B2 protein contains the ligand-binding and dimerization domains found in other nuclear hormone receptor superfamily members, but lacks the conserved DNA-binding domain. The closest relative of NR0B2 among known family members is DAX1 (NR0B1; 300473).
Northern blot analysis of human tissues by Lee et al. (1998) detected NR0B2 expression in adult small intestine, adult spleen, fetal liver, and fetal adrenal gland.
Iyer et al. (2006) stated that the N-terminal half of SHP contains 2 LxxLL nuclear receptor boxes and that the C terminus contains an activation factor (AF)-2 domain.
Seol et al. (1996) found that Nr0b2 interacted with several conventional and orphan members of the receptor superfamily, including retinoid receptors RAR (see 180240) and RXR (see 180245), thyroid hormone receptor (see 190160), and the orphan receptor MB67, in vitro and in a yeast 2-hybrid system. In mammalian cells, Nr0b2 specifically inhibited transactivation by the superfamily members with which it interacted. Seol et al. (1996) suggested that NR0B2 functions as a negative regulator of receptor-dependent signaling pathways.
The catabolism of cholesterol into bile acids is regulated by oxysterols and bile acids, which induce or repress transcription of the pathway's rate-limiting enzyme, CYP7A1 (118455). The nuclear receptor LXR-alpha (LXRA, or NR1H3; 602423) binds oxysterols and mediates feed-forward induction. Lu et al. (2000) showed that repression is coordinately regulated by a triumvirate of nuclear receptors, including the bile acid receptor, FXR (NR1H4; 603826); the promoter-specific activator, LRH1 (NR5A2; 604453); and the promoter-specific repressor, SHP. Feedback repression of CYP7A1 is accomplished by the binding of bile acids to FXR, which leads to transcription of SHP. Elevated SHP protein then inactivates LRH1 by forming a heterodimeric complex that leads to promoter-specific repression of both CYP7A1 and SHP. These results revealed an elaborate autoregulatory cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism.
Goodwin et al. (2000) used a potent, nonsteroidal FXR ligand to show that FXR induced expression of SHP1. SHP1 repressed expression of CYP7A1 by inhibiting the activity of LRH1, an orphan nuclear receptor that regulates CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
Iyer et al. (2006) showed that epitope-tagged SHP formed homodimers in the nucleus of transfected HEK293 cells. The homodimers dissociated upon heterodimerization of SHP with ligand-activated ER-alpha (ESR1; 133430). SHP also formed heterodimers in the nucleus with DAX1, and the LxxLL motifs and AF2 domain of DAX1 contributed to SHP-DAX1 heterodimerization.
Iyer et al. (2007) showed that the LxxLL motifs and AF2 domain of epitope-tagged SHP interacted to form antiparallel homodimers of SHP. The LxxLL motifs and AF2 domain of SHP were also involved in heterodimerization with DAX1.
Lee et al. (1998) isolated the human NR0B2 genomic sequence. The NR0B2 gene contains 2 exons, which are interrupted by an approximately 1.8-kb intron.
By analysis of a somatic cell hybrid mapping panel, Lee et al. (1998) mapped the NR0B2 gene to chromosome 1. They localized the NR0B2 gene to 1p36.1 using FISH.
The ability of the SHP protein to modulate the transcriptional activity of the protein that is abnormal in MODY1 (125850), namely hepatocyte nuclear receptor HNF4-alpha (600281), suggested SHP as a candidate MODY gene. Nishigori et al. (2001) screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in the SHP gene and found 5 different mutations in 6 subjects as well as 1 apparent polymorphism, all present in heterozygous state. All of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X 604630.0001 and A195S 604630.0002) and 2 additional mutations were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins showed that the mutations result in the loss of SHP activity. These results suggested that genetic variation in the SHP gene contributes to increased body weight and revealed a pathway leading to this common metabolic disorder in Japanese.
Since variations of the NR0B2 gene had been found to be associated with obesity among Japanese (Nishigori et al., 2001), Echwald et al. (2004) evaluated the prevalence of NR0B2 variants among obese Danish men. They concluded that in contrast to reported findings among obese Japanese, functional variants are rare among Danish men.
Kerr et al. (2002) and Wang et al. (2002) found that Shp-null mice maintained on standard laboratory chow appeared normal, were fertile, and had normal life spans. Loss of Shp caused abnormal accumulation and increased synthesis of bile acids due to derepression of rate-limiting Cyp7a1 and Cyp8b1 (602172) hydroxylase enzymes in the bile acid synthetic pathway. However, Shp-null mice fed bile acids efficiently repressed Cyp7a1, Cyp7b1 (603711), and Cyp8b1. Kerr et al. (2002) and Wang et al. (2002) concluded that bile acid synthesis can be regulated in the absence of Shp.
Using RT-PCR, Volle et al. (2007) found that mouse Shp was expressed at low levels in whole testis, but its expression was significantly higher in the interstitial compartment, including steroidogenic Leydig cells, compared with tubular cells. Shp-knockout mice showed increased testicular testosterone synthesis that was independent of the hypothalamus-pituitary axis. Using both genetic and pharmacologic studies in mice, Volle et al. (2007) showed that Shp inhibited expression of steroidogenic genes in the interstitial compartment by inhibiting expression of steroidogenic factor-1 (SF1, or NR5A1; 184757) and Lrh1 and by directly repressing the transcriptional activity of Lrh1. Independent of its action on androgen synthesis, Shp also determined the timing of germ cell differentiation by controlling testicular retinoic acid metabolism. By inhibiting the transcriptional activity of retinoic acid receptors, Shp controlled expression of Stra8 (609987), which is indispensable for germ cell meiosis and differentiation.
In a screening of 173 unrelated Japanese subjects with early-onset diabetes, Nishigori et al. (2001) identified 5 mutations in the NR0B2 gene, including an arg34-to-ter (R34X) mutation, in 6 moderately obese (see 601665) subjects. All of the mutations were present in heterozygous state and were found on further study to segregate with mild obesity rather than with diabetes. The R34X nonsense mutation was found also in 6 of 101 unrelated nondiabetic subjects with early-onset obesity.
Nishigori et al. (2001) found an ala195-to-ser (A195S) missense mutation in the NR0B2 gene in mildly obese (see 601665) Japanese subjects with early-onset diabetes. The authors showed that the mutation segregated with early-onset mild obesity rather than with diabetes.
Echwald, S. M., Andersen, K. L., Sorensen, T. I. A., Larsen, L. H., Andersen, T., Tonooka, N., Tomura, H., Takeda, J., Pedersen, O. Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G-A (p.G93D) variant with reduced functional activity. Hum. Mutat. 24: 381-387, 2004. [PubMed: 15459958] [Full Text: https://doi.org/10.1002/humu.20090]
Goodwin, B., Jones, S. A., Price, R. R., Watson, M. A., McKee, D. D., Moore, L. B., Galardi, C., Wilson, J. G., Lewis, M. C., Roth, M. E., Maloney, P. R., Willson, T. M., Kliewer, S. A. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Molec. Cell 6: 517-526, 2000. [PubMed: 11030332] [Full Text: https://doi.org/10.1016/s1097-2765(00)00051-4]
Iyer, A. K., Zhang, Y.-H., McCabe, E. R. B. Dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1) (NR0B1) and small heterodimer partner (SHP) (NR0B2) form homodimers individually, as well as DAX1-SHP heterodimers. Molec. Endocr. 20: 2326-2342, 2006. [PubMed: 16709599] [Full Text: https://doi.org/10.1210/me.2005-0383]
Iyer, A. K., Zhang, Y.-H., McCabe, E. R. B. LXXLL motifs and AF-2 domain mediate SHP (NR0B2) homodimerization and DAX1 (NR0B1)-DAX1A heterodimerization. Molec. Genet. Metab. 92: 151-159, 2007. [PubMed: 17686645] [Full Text: https://doi.org/10.1016/j.ymgme.2007.06.009]
Kerr, T. A., Saeki, S., Schneider, M., Schaefer, K., Berdy, S., Redder, T., Shan, B., Russell, D. W., Schwarz, M. Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev. Cell 2: 713-720, 2002. [PubMed: 12062084] [Full Text: https://doi.org/10.1016/s1534-5807(02)00154-5]
Lee, H.-K., Lee, Y.-K., Park, S.-H., Kim, Y.-S., Park, S. H., Lee, J. W., Kwon, H.-B., Soh, J., Moore, D. D., Choi, H.-S. Structure and expression of the orphan nuclear receptor SHP gene. J. Biol. Chem. 273: 14398-14402, 1998. [PubMed: 9603951] [Full Text: https://doi.org/10.1074/jbc.273.23.14398]
Lu, T. T., Makishima, M., Repa, J. J., Schoonjans, K., Kerr, T. A., Auwerx, J., Mangelsdorf, D. J. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Molec. Cell 6: 507-515, 2000. [PubMed: 11030331] [Full Text: https://doi.org/10.1016/s1097-2765(00)00050-2]
Nishigori, H., Tomura, H., Tonooka, N., Kanamori, M., Yamada, S., Sho, K., Inoue, I., Kikuchi, N., Onigata, K., Kojima, I., Kohama, T., Yamagata, K., and 9 others. Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc. Nat. Acad. Sci. 98: 575-580, 2001. [PubMed: 11136233] [Full Text: https://doi.org/10.1073/pnas.98.2.575]
Seol, W., Choi, H.-S., Moore, D. D. An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272: 1336-1339, 1996. [PubMed: 8650544] [Full Text: https://doi.org/10.1126/science.272.5266.1336]
Volle, D. H., Duggavathi, R., Magnier, B. C., Houten, S. M., Cummins, C. L., Lobaccaro, J.-M. A., Verhoeven, G., Schoonjans, K., Auwerx, J. The small heterodimer partner is a gonadal gatekeeper of sexual maturation in male mice. Genes Dev. 21: 303-315, 2007. [PubMed: 17289919] [Full Text: https://doi.org/10.1101/gad.409307]
Wang, L., Lee, Y.-K., Bundman, D., Han, Y., Thevananther, S., Kim, C.-S., Chua, S. S., Wei, P., Heyman, R. A., Karin, M., Moore, D. D. Redundant pathways for negative feedback regulation of bile acid production. Dev. Cell 2: 721-731, 2002. [PubMed: 12062085] [Full Text: https://doi.org/10.1016/s1534-5807(02)00187-9]