Alternative titles; symbols
HGNC Approved Gene Symbol: RORB
Cytogenetic location: 9q21.13 Genomic coordinates (GRCh38): 9:74,497,335-74,693,177 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q21.13 | {Epilepsy, idiopathic generalized, susceptibility to, 15} | 618357 | Autosomal dominant | 3 |
ROR-beta is a transcription factor and belongs to the nuclear receptor family (Carlberg et al., 1994). Members of this superfamily share a common modular structure composed of a transactivation domain, a DNA-binding domain, and a ligand-binding domain (Evans, 1988). Typically, their transcriptional transactivation function is regulated by small lipophilic molecules, such as steroid hormones, vitamin D, retinoic acids, and thyroid hormone. These molecules are synthesized in the organism and pass readily through the plasma membrane to reach the corresponding receptors inside the cell. In addition to the classic hormone receptors, a number of nuclear receptors for which no ligands are known have been identified by homology cloning. These nuclear receptors are referred to as 'orphan' nuclear receptors. ROR-beta is such an orphan nuclear receptor, forming a subfamily with the closely related nuclear receptors ROR-alpha (RORA; 600825) and ROR-gamma (RORC; 602943).
Carlberg et al. (1994) reported the complete cDNA sequences of RORA and RORB. They cloned the RORB gene from a rat brain library and found that it encoded a 459-amino acid polypeptide. Northern blot analysis revealed that RORB is expressed as transcripts of 10 kb and 2.4 kb in brain; transcripts were not detected in any other tissues.
Using in vitro binding assays, Carlberg et al. (1994) showed that RORB can bind either as a monomer or as a homodimer to the retinoic acid response element. On either monomeric or homodimeric binding sites, RORB shows transactivational activity that is enhanced by serum.
Baler et al. (1996) found that Rzr-beta showed a strong daily rhythm of expression in rat pineal gland. Expression was under photoneural regulation and involved an adrenergic-cAMP mechanism.
Paravicini et al. (1996) used the yeast 2-hybrid system to isolate proteins that bind to RORB. They found that both RORB and RORA interact with NM23-2 (156491), a nucleoside diphosphate kinase involved in organogenesis and differentiation.
Using a systems-biologic approach based on genomic, molecular, and cell biologic techniques, Ueda et al. (2002) profiled suprachiasmatic nuclei and liver genomewide expression patterns under light/dark cycles and constant darkness. Ueda et al. (2002) determined transcription start sites of human orthologs for newly identified cycling genes and then performed bioinformatic searches for relationships between time of day-specific expression and transcription factor response elements around transcription start sites. Ueda et al. (2002) demonstrated the role of the Rev-ErbA (602408)/ROR response element in gene expression during circadian night, which is in phase with BMAL1 (602550) and in antiphase to PER2 (603426) oscillations. Ueda et al. (2002) verified their observations using an in vitro validation system in which cultured fibroblasts transiently transfected with clock-controlled reporter vectors exhibited robust circadian bioluminescence. Ueda et al. (2002) found 7 cycling genes in the suprachiasmatic nucleus with putative cAMP response elements (CRE:TGACGT) in the promoter regions of their orthologs, the phases of which consolidate to subjective day. Ueda et al. (2002) also found 10 cycling genes in the suprachiasmatic nucleus with putative Rev-ErbA/ROR response elements (AGGTCA), to which Rev-ErbA and ROR family members bind, in the promoter regions of their orthologs. The 10 genes identified included BMAL1 and E4BP4 (605327), which displayed similar circadian expression antiphase to PER2 oscillations in both suprachiasmatic nucleus and liver. Ueda et al. (2002) found that Rev-ErbA, Rev-ErbA-beta, ROR-alpha, and ROR-beta displayed similar circadian expression profiles in the suprachiasmatic nucleus, with peaks during the day and troughs during the night, whereas ROR-gamma was not detected in the suprachiasmatic nucleus throughout the 24-hour cycle.
Toward a system-level understanding of the transcriptional circuitry regulating circadian clocks, Ueda et al. (2005) identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of the transcriptional dynamics. Ueda et al. (2005) found that E boxes (CACGTG) and E-prime boxes (CACGTT) controlled the expression of Per1 (602260), Nr1d2 (602304), Per2, Nr1d1, Dbp (124097), Bhlhb2 (604256), and Bhlhb3 (606200) transcription following a repressor-precedes-activator pattern, resulting in delayed transcriptional activity. RevErbA/ROR (600825)-binding elements regulated the transcriptional activity of Arntl (602550), Npas2 (603347), Nfil3 (605327), Clock (601851), Cry1 (601933), and Rorc (602943) through a repressor-precedes-activator pattern as well. DBP/E4BP4-binding elements controlled the expression of Per1, Per2, Per3 (603427), Nr1d1, Nr1d2, Rora, and Rorb (601972) through a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Ueda et al. (2005) suggested that regulation of E/E-prime boxes is a topologic vulnerability in mammalian circadian clocks, a concept that had been functionally verified using in vitro phenotype assay systems.
By fluorescence in situ hybridization, Andre et al. (1998) mapped the human RORB gene to 9q22, which is within the region syntenic to mouse chromosome 4.
In 4 affected members of a 4-generation French family with susceptibility to idiopathic generalized epilepsy-15 (EIG15; 618357), Rudolf et al. (2016) identified a heterozygous nonsense mutation in the RORB gene (R66X; 601972.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed that the mutant transcript escaped nonsense-mediated mRNA decay, but no mutant protein was detected in the nucleoplasm of transfected COS7 cells, consistent with a loss of function. There was evidence of possible incomplete penetrance and/or phenocopies within the family. Three additional unrelated patients with a similar phenotype were found to have de novo heterozygous point mutations or intragenic deletions in the RORB gene (601972.0002-601972.0004). Molecular modeling suggested that some of these mutations would interfere with DNA binding or be pathogenic; additional functional studies of the variants and studies of patients cells were not performed. Three additional patients with a similar phenotype who had larger or more complex deletions or translocations involving the RORB gene were also identified, suggesting that RORB plays a role in neurodevelopment and possibly neuronal hyperexcitability.
ROR-beta is expressed in areas of the central nervous system that are involved in the processing of sensory information, including spinal cord, thalamus, and sensory cerebellar cortices. Additionally, ROR-beta localizes to the 3 principal anatomic components of the mammalian timing system: the suprachiasmatic nuclei, the retina, and the pineal gland. Andre et al. (1998) showed that RORB mRNA levels oscillate in retina and pineal gland with a circadian rhythm that persists in constant darkness. They generated RORB-deficient mice by gene targeting in embryonic stem cells and analyzed their phenotypic behavior. Rorb -/- mice display a duck-like gait, transient male incapability to reproduce sexually, and a severely disorganized retina that suffers from postnatal degeneration. Consequently, adult Rorb -/- mice are blind, yet their circadian activity rhythm is still entrained by light-dark cycles. Under conditions of constant darkness, Rorb -/- mice display an extended period of free-running rhythmicity. The overall behavioral phenotype of Rorb -/- mice, together with the chromosomal localization of the gene on mouse chromosome 4, suggested a close relationship to the spontaneous mouse mutation 'vacillans' described by Sirlin (1956) and now thought to be extinct.
Carneiro et al. (2021) identified a splice-site mutation at the end of exon 9 of the Rorb gene as the cause of abnormal locomotion in the 'sauteur d'Alfort' rabbit, which exhibits bipedal gait using the front legs instead of typical jumping. The mutation caused a marked reduction of Rorb-positive neurons in spinal cord and defects in differentiation of populations of spinal cord interneurons.
In 4 affected members (patients 4, 13, 14, and 20) of a 4-generation French family with susceptibility to idiopathic generalized epilepsy-15 (EIG15; 618357), Rudolf et al. (2016) identified a heterozygous c.196C-T transition (c.196C-T, NM_006914.3) in exon 3 of the RORB gene, resulting in an arg66-to-ter (R66X) substitution. The variant led to termination of the 2 isoforms (R66X in RORB1 and R77X in RORB2). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Patient cells showed that the mutant transcript escaped nonsense-mediated mRNA decay, but no mutant protein was detected in the nucleoplasm of transfected COS7 cells, consistent with a loss of function. There was evidence of possible incomplete penetrance and/or phenocopies: the variant was also found in a family member (patient 10) who had only isolated photoparoxysmal response (PPR) during intermittent photic stimulation (IPS), but whose seizure state could not be confirmed, and in another family member (patient 23) who refused EEG investigations. In addition, there were 3 family members (11, 15, and 21) who had isolated PPR during IPS, but they did not carry the variant.
In an 18-year-old woman (patient AG1) with idiopathic generalized epilepsy-15 (EIG15; 618357), Rudolf et al. (2016) identified a de novo heterozygous c.218T-C transition (c.218T-C, NM_006914.3) in the RORB gene, resulting in a leu73-to-pro (L73P) substitution in the DNA-binding domain. The mutation, which was found by trio-based exome sequencing, was predicted to interfere with DNA binding by analysis of structural modeling. Functional studies of the variant and studies of patient cells were not performed.
In a boy (patient RO1) with idiopathic generalized epilepsy-15 (EIG15; 618357), Rudolf et al. (2016) identified a de novo heterozygous 3-bp deletion in the RORB gene (c.1249_1251delACG, NM_006914.3), resulting in the deletion of residue thr417 (thr417del). Molecular modeling predicted that the mutation would interfere with proper RORB cofactor binding, potentially resulting in disruption of DNA ligand binding, as well as possible destabilization of the mutant protein. Functional studies of the variant and studies of patient cells were not performed.
In a 10-year-old girl (GE0705) with idiopathic generalized epilepsy-15 (EIG15; 618357), Rudolf et al. (2016) identified a de novo heterozygous 52-kb intragenic deletion (chr9.77261322_77313598del, GRCh37) in the RORB gene, resulting in the deletion of exons 5 to 10. The patient was identified though array-CGH sequencing. Functional studies of the variant and studies of patient cells were not performed.
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Baler, R., Coon, S., Klein, D. C. Orphan nuclear receptor RZR-beta: cyclic AMP regulates expression in the pineal gland. Biochem. Biophys. Res. Commun. 220: 975-978, 1996. [PubMed: 8607878] [Full Text: https://doi.org/10.1006/bbrc.1996.0517]
Carlberg, C., Hooft van Huijsduijnen, R., Staple, J. K., DeLamarter, J. F., Becker-Andre, M. RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. Molec. Endocr. 8: 757-770, 1994. [PubMed: 7935491] [Full Text: https://doi.org/10.1210/mend.8.6.7935491]
Carneiro, M., Vieillard, J., Andrade, P., Boucher, S., Afonso, S., Blanco-Aguiar, J. A., Santos, N., Branco, J., Esteves, P. J., Ferrand, N., Kullander, K., Andersson, L. A loss-of-function mutation in RORB disrupts saltatorial locomotion in rabbits. PLoS Genet. 17: e1009429, 2021. [PubMed: 33764968] [Full Text: https://doi.org/10.1371/journal.pgen.1009429]
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Paravicini, G., Steinmayr, M., Andre, E., Becker-Andre, M. The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily. Biochem. Biophys. Res. Commun. 227: 82-87, 1996. [PubMed: 8858107] [Full Text: https://doi.org/10.1006/bbrc.1996.1471]
Rudolf, G., Lesca, G., Mehrjouy, M. M., Labalme, A., Salmi, M., Bache, I., Bruneau, N., Pendziwiat, M., Fluss, J., de Bellescize, J., Scholly, J., Moller, R. S., and 29 others. Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. Europ. J. Hum. Genet. 24: 1761-1770, 2016. [PubMed: 27352968] [Full Text: https://doi.org/10.1038/ejhg.2016.80]
Sirlin, J. L. Vacillans, a neurological mutant in the house mouse linked with brown. J. Genet. 54: 42-48, 1956.
Ueda, H. R., Chen, W., Adachi, A., Wakamatsu, H., Hayashi, S., Takasugi, T., Nagano, M., Nakahama, K., Suzuki, Y., Sugano, S., Iino, M., Shigeyoshi, Y., Hashimoto, S. A transcription factor response element for gene expression during circadian night. Nature 418: 534-539, 2002. [PubMed: 12152080] [Full Text: https://doi.org/10.1038/nature00906]
Ueda, H. R., Hayashi, S., Chen, W., Sano, M., Machida, M., Shigeyoshi, Y., Iino, M., Hashimoto, S. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nature Genet. 37: 187-192, 2005. [PubMed: 15665827] [Full Text: https://doi.org/10.1038/ng1504]