Alternative titles; symbols
HGNC Approved Gene Symbol: RORA
Cytogenetic location: 15q22.2 Genomic coordinates (GRCh38): 15:60,488,284-61,229,302 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q22.2 | Intellectual developmental disorder with or without epilepsy or cerebellar ataxia | 618060 | Autosomal dominant | 3 |
Becker-Andre et al. (1993) considered the gene they termed RZR-alpha (RZRA) to be a member of a new subfamily of the steroid hormone nuclear receptor superfamily, which includes receptors for steroids, retinoids, and thyroid hormones, as well as a large number of related 'orphan' receptors, so named because their ligands are unknown. Becker-Andre et al. (1993) identified RZRA by degenerate PCR on human endothelial cell RNA. The sequence of this receptor shares 70% identity with the alpha form of the retinoic acid receptor (RARA; 180240). Northern blot analysis detected RZRA expression primarily as a 15-kb mRNA in most organs tested, with highest expression in peripheral blood leukocytes. Other bands corresponding more closely to RZRA's 468-amino acid coding sequence length were also found.
Giguere et al. (1994) identified ROR-alpha (RORA) from a rat brain cDNA library using the DNA-binding domain of human RARA as a probe. In rats, 4 different isoforms were identified that result from alternative splicing. Each isoform shares common DNA-binding and putative ligand-binding domains but with distinct N-terminal sequences. The alpha-1 and alpha-2 isoforms bind to hormone response elements, but have different specificities. The alpha-2 isoform contains a functionally important subdomain within an exon that is located on the minus strand of a cytochrome c-processed pseudogene.
Carlberg et al. (1994) reported the complete cDNA sequences of RZRA and RZRB (RORB; 601972). Using in vitro binding assays, Carlberg et al. (1994) showed that RZRA can bind either as a monomer or as a homodimer to the retinoic acid response element. On either monomeric or homodimeric binding sites, RZRA shows transactivational activity that is enhanced by serum.
Giguere et al. (1995) used a human ROR-alpha-1 cDNA to map the gene to chromosome 15q21-q22 by fluorescence in situ hybridization. By interspecific backcross mapping analysis, they mapped the mouse gene to the central region of mouse chromosome 9.
Meyer et al. (2000) showed that the RORA gene and the RORC (602943) gene, but not the RORB gene, are expressed in mesenchymal stem cells derived from bone marrow. Cells undergoing osteogenic differentiation showed increased messenger signal expression. They found that homozygous 'staggerer' mutants have thin long bones compared with heterozygous animals and wildtype littermates and that the bones of sg/sg animals are osteopenic. They concluded that the product of the Rora gene most likely acts by direct modulation of a bone matrix component.
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, RORA, and RORB displayed similar circadian expression profiles in the suprachiasmatic nucleus, with peaks during the day and troughs during the night, whereas RORC was not detected in the suprachiasmatic nucleus throughout the 24-hour cycle.
Coste and Rodriguez (2002) determined that REV-ERB-alpha transfected and expressed in human hepatic cells specifically repressed APOC3 (107720) promoter activity. By deletion and site-directed mutagenesis experiments, they showed that REV-ERB-alpha bound to an element in the proximal promoter of the APOC3 gene that is also a ROR-alpha-1 element. They provided evidence for cross-talk between REV-ERB-alpha and ROR-alpha-1 in modulating the APOC3 promoter.
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-binding elements regulated the transcriptional activity of Arntl (602550), Npas2 (603347), Nfil3, Clock (601851), Cry1 (601933), and Rorc 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 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.
Spinocerebellar ataxia-1 (SCA1; 164400) is a neurodegenerative disease caused by expansion of a CAG trinucleotide repeat encoding a polyglutamine stretch in ataxin-1 (ATXN1; 601556). Using a conditional transgenic mouse model of SCA1, Serra et al. (2006) showed that delaying postnatal expression of mutant human ATXN1 until completion of cerebellar maturation led to a substantial reduction in disease severity in adults compared with early postnatal expression of mutant ATXN1. Microarray analysis revealed that genes regulated by Rora were downregulated at an early stage of disease in Purkinje cells of SCA1 transgenic mice. Rora mRNA and protein levels were reduced in Purkinje cells of SCA1 transgenic mice, and the effect of mutant ATXN1 on Rora protein levels appeared to be independent of its effect on Rora mRNA levels. Partial loss of Rora enhanced the pathogenicity of mutant ATXN1 in transgenic mice. Coimmunoprecipitation and pull-down analyses suggested the existence of a complex containing Atxn1, Rora, and the Rora coactivator Tip60 (HTATIP; 601409), with Atxn1 and Tip60 interacting directly. Serra et al. (2006) concluded that RORA and TIP60 have a role in SCA1 and proposed that their findings provide a mechanism by which compromised cerebellar development contributes to the severity of neurodegeneration in an adult.
Solt et al. (2011) presented SR1001, a high-affinity synthetic ligand--the first in a new class of compound--that is specific to both ROR-alpha and ROR-gamma-t (602943) and which inhibits TH17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of ROR-alpha and ROR-gamma-t, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix-12 and leads to diminished affinity for coactivators and increased affinity for corepressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine TH17 cells, as demonstrated by inhibition of interleukin-17A (603149) gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human TH17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Solt et al. (2011) concluded that their data demonstrated the feasibility of targeting the orphan receptors ROR-alpha and ROR-gamma-t to inhibit specifically TH17 cell differentiation and function, and indicated that this novel class of compound has potential utility in the treatment of autoimmune diseases.
By quantitative RT-PCR analysis, Matsuoka et al. (2017) showed that CLDND1 (619677) expression and ROR-alpha expression were directly correlated at the transcription level in rat tissues and human cell cultures. ROR-alpha activated CLDND1 transcription by binding to the ROR-alpha response element in the promoter region of CLDND1. Knockdown of ROR-alpha reduced CLDND1 transcription in human brain endothelial cells.
Choi et al. (2019) showed that the CH25H (604551)-CYP7B1 (603711)-ROR-alpha axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. They found that mouse osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1), and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, ROR-alpha was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. Choi et al. (2019) concluded that their results indicated that osteoarthritis is a disease associated with metabolic disorders and suggested that targeting the CH25H-CYP7B1-ROR-alpha axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.
In 11 unrelated patients with intellectual developmental disorder with or without epilepsy and cerebellar ataxia (IDDECA; 618060), Guissart et al. (2018) identified heterozygous mutations in the RORA gene (see, e.g., 600825.0001-600825.0005). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing when possible. All mutations were confirmed to occur de novo, except in 1 adopted patient. The patients were ascertained through collaboration between several research centers. There were 5 missense mutations, 4 frameshift mutations, a splice site mutation, and a nonsense mutation. Two of the missense variants (S409R and R462Q) mapped to the ligand-binding domain, and 3 (G92A, K94R, and C90S) mapped to the DNA-binding domain. Knockdown of the zebrafish ortholog of the rora gene (roraa) resulted in decreased cerebellar volume with a decreased size of Purkinje and granule cell layers compared to wildtype. In vivo complementation studies in roraa-null zebrafish showed that wildtype human RORA could rescue the cerebellar phenotype. Expression of 2 of the human missense mutations in the DNA-binding domain (G92A and K94R) resulted in early developmental defects, including increased mortality, reduction in the size of anterior structures, and tail extension failure. The phenotype was more severe than the morphant phenotype, suggesting a dominant toxic effect. In contrast, expression of the R462Q missense variant in the ligand-binding domain did not cause morphologic defects and did not rescue the cerebellar defect, suggesting that this mutation resulted in a loss of function. Guissart et al. (2018) suggested that the mutations have different pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect depending on their localization in the ligand-binding domain or the DNA-binding domain, respectively. Patients with loss-of-function mutations tended to have mild intellectual disability with autistic features, whereas 3 individuals with potentially dominant toxic variants had more severe intellectual disability, ataxia, and cerebellar atrophy. However, there was significant phenotypic overlap among the patients.
The recessive mouse mutation 'staggerer' (sg) is associated with severe cerebellar ataxia due to a cell-autonomous defect in the development of Purkinje cells. These cells are reduced in numbers and show immature morphology, synaptic arrangement, biochemical properties, and gene expression. In addition, sg heterozygotes show accelerated dendritic atrophy and cell loss, suggesting that sg has a role in mature Purkinje cells. Certain functions of the immune system are also affected. Hamilton et al. (1996) mapped sg to a 160-kb interval on mouse chromosome 9 that was found to contain the gene encoding Rora, a member of the nuclear hormone receptor superfamily. Furthermore, sg mice were found to carry a deletion within the Rora gene that prevents translation of the ligand-binding homology domain. Based on these results, they proposed a model in which Rora interacts with the thyroid hormone signaling pathway to induce Purkinje cell maturation. Of the 4 different isoforms of the Rora gene that are generated by a combination of alternative promoter usage and exon splicing and that differ in their DNA-binding properties, Matysiak-Scholze and Nehls (1997) found that isoforms Rora1 and Rora4 are specifically coexpressed in the murine cerebellum and human cerebellum. Thus, at least 2 isoforms of the murine Rora gene are affected by the genomic deletion associated with the sg phenotype. The finding of cerebellum-specific coregulation of Rora1 and Rora4 suggested that distinct sets of target genes regulated by the Rora1 and Rora4 isoforms are required for Purkinje cell development.
In a 10-year-old French girl (patient 6) with intellectual developmental disorder with epilepsy and cerebellar ataxia (IDDECA; 618060), Guissart et al. (2018) identified a de novo heterozygous 1-bp deletion (c.1019delG, NM_134261.2) in exon 7 of the RORA gene, resulting in a frameshift and premature termination (Arg340ProfsTer17) within the ligand-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD or Exome Variant Server database. Patient fibroblasts showed normal levels of RORA protein, suggesting that the mutation did not result in nonsense-mediated mRNA decay. However, the mutation was predicted to result in partial truncation of the ligand-binding domain. Guissart et al. (2018) hypothesized that this mutation could result in a dominant toxic effect.
In a 3-year-old girl (patient 5) with intellectual developmental disorder with epilepsy and mild cerebellar ataxia (IDDECA; 618060), Guissart et al. (2018) identified a de novo heterozygous 2-bp deletion (c.804_805delGT, NM_134261.2) in the RORA gene, resulting in a frameshift and premature termination (Ser269HisfsTer13). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was predicted to result in complete truncation of the ligand-binding domain and/or nonsense-mediated mRNA decay and haploinsufficiency.
In a 4-year-old German boy (patient 8) with intellectual developmental disorder without epilepsy or cerebellar ataxia (IDDECA; 618060), Guissart et al. (2018) identified a de novo heterozygous c.1385G-A transition (c.1385G-A, NM_134261.2) in exon 10 of the RORA gene, resulting in an arg462-to-gln (R462Q) substitution at a conserved residue in the ligand-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD, ExAC, or Exome Variant Server databases.
In a 3.5-year-old boy from Estonia (patient 2) with intellectual developmental disorder without epilepsy and with cerebellar ataxia (IDDECA; 618060), Guissart et al. (2018) identified a de novo heterozygous c.275G-C transversion (c.275G-C, NM_134261.2) in exon 3 of the RORA gene, resulting in a gly92-to-ala (G92A) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD, ExAC, or Exome Variant Server databases.
In a 6-year-old French girl (patient 3) with intellectual developmental disorder with epilepsy and cerebellar ataxia (IDDECA; 618060), Guissart et al. (2018) identified a de novo heterozygous c.281A-G transition (c.281A-G, NM_134261.2) in exon 3 of the RORA gene, resulting in a lys94-to-arg (K94R) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD, ExAC, or Exome Variant Server databases.
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