|Coordinate||94,397,302 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||RAR-related orphan receptor gamma|
|Synonym(s)||Thor, thymus orphan receptor, RORgamma|
|Chromosomal Location||94,372,794-94,398,276 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a DNA-binding transcription factor and is a member of the NR1 subfamily of nuclear hormone receptors. The specific functions of this protein are not known; however, studies of a similar gene in mice have shown that this gene may be essential for lymphoid organogenesis and may play an important regulatory role in thymopoiesis. In addition, studies in mice suggest that the protein encoded by this gene may inhibit the expression of Fas ligand and IL2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
PHENOTYPE: Homozygotes for targeted null mutations exhibit lack of peripheral and mesenteric lymph nodes and Peyer's patches, reduced numbers of thymocytes, and increased apoptosis with loss of thymic expression of anti-apoptosic factor Bcl-xL. [provided by MGI curators]
|Amino Acid Change||Tyrosine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000029795] [ENSMUSP00000143763] [ENSMUSP00000143610]|
AA Change: Y500*
|Predicted Effect||probably null|
AA Change: Y479*
|Predicted Effect||probably null|
AA Change: Y331*
|Predicted Effect||probably null|
|Meta Mutation Damage Score||0.9755|
|Is this an essential gene?||Probably essential (E-score: 0.805)|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.923; ML prob: 0.884; human score: 1|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2019-09-04 9:47 PM by Diantha La Vine|
|Record Created||2014-12-19 12:03 PM by Jin Huk Choi|
The macadamias phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R1470, some of which showed a diminished T-dependent antibody response to recombinant Semliki Forest virus (rSFV)-encoded β-galactosidase (rSFV-β-gal) (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 145 mutations. The reduced T-dependent antibody response to rSFV-β-gal was linked by continuous variable mapping to a mutation in Rorc: a T to A transversion at base pair 94,397,302 (v38) on chromosome 3, or base pair 24,587 in the GenBank genomic region NC_000069. Linkage was found with a recessive model of inheritance (P = 8.697 x 10-8), wherein 4 variant homozygotes departed phenotypically from 8 homozygous reference mice and 11 heterozygous mice (Figure 2). A substantial semidominant effect was observed but the mutation is preponderantly recessive. The mutation corresponds to residue 1,598 in the mRNA sequence NM_011281 within exon 11 of 11 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of tyrosine 500 for a premature stop codon (Y500*) in the RAR-related orphan receptor gamma (RORγ) protein.
|Illustration of Mutations in
Gene & Protein
RAR-related orphan receptor gamma (RORγ) is a member of the RAR-related orphan nuclear hormone receptor transcription factor family. RORγ has an N-terminal domain (A/B region), a DNA-binding domain (DBD), a hinge domain, and a C-terminal ligand-binding domain (LBD) [Figure 3; reviewed in (1)]. Rorc generates two isoforms of RORγ, RORγ1 and RORγt (alternatively, RORγ2), by the use of alternative promoters and/or by alternative splicing of a common pre-mRNA (2;3). The RORγ isoforms have the same DBDs and LBDs, but RORγt lacks the N-terminal 24 amino acids of RORγ1 encoded by the first two exons of Rorc and has three alternative residues encoded by the first exon specific to RORγt [Figure 3; (2;3)].
The macadamias mutation results in substitution of Tyr500 for a premature stop codon in the RORγ1 isoform as well as a substitution of Tyr497 for a premature stop codon in the RORγt isoform. The mutated residue in both isoforms is within an undefined domain after the LBD (SMART). Protein expression and localization of RORγmacadamias has not been examined.
Please see the record for chestnut for more information about Rorc.
RORγ has well documented functions including to negatively regulate CD4+CD8+ double positive (DP) thymocyte apoptosis to promote cell survival [(4;5); reviewed in (6)]. In addition, RORγ inhibits expression of Fas ligand (FasL) and interleukin-2 (IL-2), protecting hybridomas from TCR-induced apoptosis [(2;7); reviewed in (6)]. RORγt promotes TGF-β plus IL-6- or IL-21-induced TH17 differentiation and suppress TNF- and IL-1β-induced TH1 and TH2 differentiation (8-11). Rorc-/- mice do not have lymph nodes (both peripheral and mesenteric) as well as Peyer’s patches due to the absence of lymphoid tissue inducer (LTi) cells, which require RORγt for their generation and survival through the regulation of Bcl-xL (4;5;12;13). Studies have shown conflicting results on the splenic structure of Rorc-/- mice (MGI:2384142). Sun et al. reported no change in splenic structure (4), while Zhang et al. reported enlarged spleens due to an accumulation of conventional resting B cells; B lymphocyte development in the bone marrow and spleen in the Rorc-/- mice were normal and B cell levels in the blood were comparable to controls (13).
Significant changes in the frequency of T and B cells were not observed in macadamias. However, the deficiency of the macadamias mice to mount a T-dependent antibody response to rSFV-β-gal indicates that RORγmacadamias has reduced and/or altered function compared to the wild-type protein.
1) 94°C 2:00
The following sequence of 457 nucleotides is amplified (chromosome 3, + strand):
1 tggctgctca agttgggtca agggtcgggg aggcatcaag aagggtcatc ctagctcagt
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. McKenna, N. J., Xu, J., Nawaz, Z., Tsai, S. Y., Tsai, M. J., and O'Malley, B. W. (1999) Nuclear Receptor Coactivators: Multiple Enzymes, Multiple Complexes, Multiple Functions. J Steroid Biochem Mol Biol. 69, 3-12.
2. He, Y. W., Deftos, M. L., Ojala, E. W., and Bevan, M. J. (1998) RORgamma t, a Novel Isoform of an Orphan Receptor, Negatively Regulates Fas Ligand Expression and IL-2 Production in T Cells. Immunity. 9, 797-806.
3. Villey, I., de Chasseval, R., and de Villartay, J. P. (1999) RORgammaT, a Thymus-Specific Isoform of the Orphan Nuclear Receptor RORgamma / TOR, is Up-Regulated by Signaling through the Pre-T Cell Receptor and Binds to the TEA Promoter. Eur J Immunol. 29, 4072-4080.
4. Sun, Z., Unutmaz, D., Zou, Y. R., Sunshine, M. J., Pierani, A., Brenner-Morton, S., Mebius, R. E., and Littman, D. R. (2000) Requirement for RORgamma in Thymocyte Survival and Lymphoid Organ Development. Science. 288, 2369-2373.
5. Kurebayashi, S., Ueda, E., Sakaue, M., Patel, D. D., Medvedev, A., Zhang, F., and Jetten, A. M. (2000) Retinoid-Related Orphan Receptor Gamma (RORgamma) is Essential for Lymphoid Organogenesis and Controls Apoptosis during Thymopoiesis. Proc Natl Acad Sci U S A. 97, 10132-10137.
6. Dzhagalov, I., Zhang, N., and He, Y. W. (2004) The Roles of Orphan Nuclear Receptors in the Development and Function of the Immune System. Cell Mol Immunol. 1, 401-407.
7. Littman, D. R., Sun, Z., Unutmaz, D., Sunshine, M. J., Petrie, H. T., and Zou, Y. R. (1999) Role of the Nuclear Hormone Receptor ROR Gamma in Transcriptional Regulation, Thymocyte Survival, and Lymphoid Organogenesis. Cold Spring Harb Symp Quant Biol. 64, 373-381.
8. Michel, M. L., Mendes-da-Cruz, D., Keller, A. C., Lochner, M., Schneider, E., Dy, M., Eberl, G., and Leite-de-Moraes, M. C. (2008) Critical Role of ROR-Gammat in a New Thymic Pathway Leading to IL-17-Producing Invariant NKT Cell Differentiation. Proc Natl Acad Sci U S A. 105, 19845-19850.
9. Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., Weiner, H. L., and Kuchroo, V. K. (2006) Reciprocal Developmental Pathways for the Generation of Pathogenic Effector TH17 and Regulatory T Cells. Nature. 441, 235-238.
10. Ivanov, I. I., Zhou, L., and Littman, D. R. (2007) Transcriptional Regulation of Th17 Cell Differentiation. Semin Immunol. 19, 409-417.
11. Manel, N., Unutmaz, D., and Littman, D. R. (2008) The Differentiation of Human T(H)-17 Cells Requires Transforming Growth Factor-Beta and Induction of the Nuclear Receptor RORgammat. Nat Immunol. 9, 641-649.
12. Eberl, G., Marmon, S., Sunshine, M. J., Rennert, P. D., Choi, Y., and Littman, D. R. (2004) An Essential Function for the Nuclear Receptor RORgamma(t) in the Generation of Fetal Lymphoid Tissue Inducer Cells. Nat Immunol. 5, 64-73.
|Science Writers||Anne Murray|
|Authors||Kuan-Wen Wang, Jin Huk Choi, Apiruck Watthanasurorot, Bruce Beutler|