Alternative titles; symbols
HGNC Approved Gene Symbol: RARB
Cytogenetic location: 3p24.2 Genomic coordinates (GRCh38): 3:24,829,321-25,597,932 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p24.2 | Microphthalmia, syndromic 12 | 615524 | Autosomal dominant; Autosomal recessive | 3 |
From a comparison of a hepatitis-B virus (HBV) integration site present in a particular human hepatocellular carcinoma (HCC; 114550) with the corresponding unoccupied site in the nontumorous tissue of the same liver, Dejean et al. (1986) found that HBV integration placed the viral sequence next to a liver cell sequence that bears a striking resemblance to both an oncogene, ERBA (190120), and the supposed DNA-binding domain of the human glucocorticoid receptor (138040) and estrogen receptor (133430) genes. Dejean et al. (1986) suggested that this gene, HAP, which is usually silent or transcribed at a very low level in normal hepatocytes, becomes inappropriately expressed as a consequence of HBV integration, thus contributing to the cell transformation. Further studies by de The et al. (1987) suggested that the HAP gene product may be a novel ligand-responsive regulatory protein whose inappropriate expression in liver is related to hepatocellular carcinogenesis.
Brand et al. (1988) showed that the novel protein called HAP is a retinoic acid receptor. They referred to this receptor as the beta type (RARB).
The retinoic acid receptors RARA (180240) and RARB are members of the nuclear receptor superfamily. Mattei et al. (1988) noted that RARA (180240) and RARB are more homologous to the 2 closely related thyroid hormone receptors, THRA (190120) and THRB (190160), than to any other members of the nuclear receptor family.
Benbrook et al. (1988) showed a predominant distribution of RARA in epithelial tissues and therefore used the designation RAR-epsilon.
By means of a panel of rodent-human somatic cell hybrid DNAs, Dejean et al. (1986) localized the RARB gene to chromosome 3. Brand et al. (1988) mapped the RARB gene to chromosome 3p25-p21. By in situ hybridization, Mattei et al. (1988) assigned the RARB gene to chromosome 3p24.
Mattei et al. (1991) assigned the corresponding gene to chromosome 14, band A, in the mouse, and to chromosome 15 in the rat. Nadeau et al. (1992) confirmed assignment of the mouse homolog to the centromeric portion of chromosome 14.
Using deletion mapping, de The et al. (1990) identified a 27-bp fragment located 59-bp upstream of the transcriptional start, which confers retinoic acid responsiveness on the herpesvirus thymidine kinase promoter. They found indications that both alpha and beta receptors act through the same DNA sequence.
Lotan et al. (1995) found that the expression of RARB mRNA was selectively lost in premalignant oral lesions and could be restored by treatment with isotretinoin. Restoration of the expression of RARB mRNA was associated with a clinical response.
Delta oscillations, characteristic of the electroencephalogram (EEG) of slow wave sleep, estimate sleep depth and need and are thought to be closely linked to the recovery function of sleep. The cellular mechanisms underlying the generation of delta waves at the cortical and thalamic levels are well documented, but the molecular regulatory mechanisms remained elusive. Maret et al. (2005) demonstrated in the mouse that the gene encoding the retinoic acid receptor beta (Rarb) determines the contribution of delta oscillations to the sleep EEG. Maret et al. (2005) concluded that retinoic acid signaling, which is involved in the patterning of the brain and dopaminergic pathways, regulates cortical synchrony in the adult.
In a nonconsanguineous family with 4 microphthalmic sibs who had variable additional features, including diaphragmatic hernia, pulmonary hypoplasia, and cardiac abnormalities (MCOPS12; 615524), and who were known to be negative for mutation in the STRA6 gene (610745), Srour et al. (2013) performed whole-exome sequencing and identified compound heterozygosity for a nonsense mutation (R119X; 180220.0001) and a 2-bp insertion (180220.0002) in the RARB gene that segregated with disease. Analysis of RARB in 15 patients with unilateral or bilateral clinical anophthalmia or microphthalmia who also had at least 1 abnormality involving the diaphragm, heart, or lung, in whom mutation in the STRA6 gene had previously been excluded by Chassaing et al. (2013), revealed 3 unrelated individuals who were heterozygous for de novo missense mutations at the same nucleotide (R387C, 180220.0003; R387S, 180220.0004). None of the mutations were found in more than 1,000 exomes or in the 1000 Genomes Project, Exome Variant Server, or dbSNP (build 138) databases.
RARB, RARG (180190), RXRB (180246), and RXRG (180247) are expressed in the striatum. To study the effect of these genes on locomotion, Krezel et al. (1998) developed single and double knockout mice and analyzed their locomotor skills by open field and rotarod testing. RARB-RXRB, RARB-RXRG, and RXRB-RXRG double-null mutant mice, but not the corresponding single-null mutants, exhibited reductions in forward locomotion when compared with wildtype littermates. Forty percent of the RARB-RXRB-null mutants showed backward locomotion. Rotarod test performance was impaired for RARB, RARB-RXRB, RARB-RXRG, and RXRB-RXRG mice. In contrast, RARA, RARG, RARA-RXRG, and RARG-RXRG-null mice showed no defects in locomotion, even though both RARA and RARG are also expressed in the striatum. The morphology, development, and function of skeletal muscle, peripheral nerves, and spinal cord were normal in all single and double-null mutants, as were balance reflexes. These results suggested to Krezel et al. (1998) that RARB, RXRB, and RXRG are involved specifically in the control of locomotor behaviors, and that heterodimers of RARB with either RXRB or RXRG are the functional receptor units, such that RXRB and RXRG are functionally redundant. Krezel et al. (1998) studied the expression of D1 and D2 dopamine receptors (D1R; 126449 and D2R; 126450), the most abundant dopamine receptors in the striatum, in these mutant mice. RARB-RXRB, RARB-RXRG, and RXRB-RXRG double-null mutants, but not RARB or RXRG single mutants, exhibited 40% and 30% reduction in whole-striatal D1R and D2R transcripts, respectively, when compared with wildtype controls. The reduction was mostly in the medioventral regions of the striatum, including the shell and core of the nucleus accumbens, and the mediodorsal part of the caudate putamen. The reduction was not due to loss of D2R-expressing neurons; no increase in apoptosis was noted. The histology of the striatum was normal. The characterization of a retinoic acid response element in the D2R promoter by Samad et al. (1997) led Krezel et al. (1998) to suggest that the reduction in D2R and D2R expression occurs on a transcriptional level. The RARB-RXRB, RARB-RXRG, and RXRB-RXRG double-null mutants did not exhibit the normal increase in locomotion induced by cocaine, mimicking the phenotype of D1R-null mice. Taken together, these results indicated to Krezel et al. (1998) that retinoids are involved in controlling the function of the dopaminergic mesolimbic pathway and suggested that defects in retinoic acid signaling may contribute to disorders such as Parkinson disease and schizophrenia.
Mattei et al. (1988) noted that RARA and RARB are more homologous to THRA and THRB, located on chromosomes 17 and 3, respectively, than to other members of the nuclear receptor family, They suggested that the thyroid hormone and retinoic acid receptors evolved by gene, and possibly chromosome, duplications from a common ancestor that diverged rather early in evolution from the common ancestor of the steroid receptor group of the family.
Koh and Moore (1999) noted that the THRA, NR1D1 (602408), and RARA genes are linked on chromosome 17q, and that the NR1D1 gene overlaps an exon of the THRA gene on the opposite strand. They found that THRB, NR1D2 (602304), and RARB are similarly linked and oriented on chromosome 3p. The ancestral genes were duplicated before the divergence of vertebrates, since at least the TRs and RARs are also duplicated in birds and amphibians.
In a nonconsanguineous family with 4 microphthalmic sibs who also exhibited diaphragmatic hernia, pulmonary hypoplasia, and cardiac defects (MCOPS12; 615524), originally reported by Chitayat et al. (2007), Srour et al. (2013) identified compound heterozygosity for 2 mutations in the RARB gene that were both predicted to disrupt function: a c.355C-T transition causing an arg119-to-ter (R119X) substitution, predicted to result in an inactive truncated receptor lacking the second zinc finger of the DNA-binding domain and the entire ligand-binding domain; and a 2-bp insertion (c.1201_1202insCT; 180220.0002), causing substitution of a hydrophobic isoleucine with a polar serine residue and the replacement of the last 52 amino acids with an aberrant extension of 15 amino acids (Ile403SerfsTer15). The unaffected parents were each heterozygous for 1 of the RARB mutations, and an unaffected sister did not carry the mutations, neither of which was found in more than 1,000 exomes or in the 1000 Genomes Project, Exome Variant Server, or dbSNP (build 138) databases. Functional analysis in transfected HEK293 cells demonstrated that the transcriptional response to retinoic acid was completely abolished with the nonsense mutation and was impaired with the 2-bp insertion.
For discussion of the 2-bp insertion (1201_1202insCT) in the RARB gene that was found in compound heterozygous state in patients with syndromic microphthalmia-12 (MCOPS12; 615524) by Srour et al. (2013), see 180220.0001.
In a French female infant and an unrelated male fetus of Angolan and Congolese descent, who exhibited bilateral and unilateral microphthalmia, respectively, as well as pulmonary hypoplasia and left diaphragmatic hernia (MCOPS12; 615524), Srour et al. (2013) identified heterozygosity for a de novo 1159C-T transition in the RARB gene, resulting in an arg387-to-cys (R387C) substitution at a highly conserved residue. The mutation was not present in the parents, in more than 1,000 exomes, or in the 1000 Genomes Project, Exome Variant Server, or dbSNP (build 138) databases. Functional analysis in transfected HEK293 cells demonstrated that the transcriptional response to retinoic acid was significantly increased with the R387C mutant, reaching a 28-fold induction compared to 9-fold with wildtype RARB.
In a 16-year-old boy with bilateral microphthalmia, diaphragmatic hernia, and intellectual disability (MCOPS12; 615524), originally reported by Chitayat et al. (2007), Srour et al. (2013) identified heterozygosity for a de novo c.1159C-A transversion in the RARB gene, resulting in an arg387-to-ser (R387S) substitution at a highly conserved residue. The mutation was not present in the parents, in more than 1,000 exomes, or in the 1000 Genomes Project, Exome Variant Server, or dbSNP (build 138) databases. Functional analysis in transfected HEK293 cells demonstrated that the transcriptional response to retinoic acid was significantly increased with the R387S mutant, reaching a 23-fold induction compared to 9-fold with wildtype RARB.
Benbrook, D., Lernhardt, E., Pfahl, M. A new retinoic acid receptor identified from a hepatocellular carcinoma. (Letter) Nature 333: 669-672, 1988. [PubMed: 2836738] [Full Text: https://doi.org/10.1038/333669a0]
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Chassaing, N., Ragge, N., Kariminejad, A., Buffet, A., Ghaderi-Sohi, S., Martinovic, J., Calvas, P. Mutation analysis of the STRA6 gene in isolated and non-isolated anophthalmia/microphthalmia. Clin. Genet. 83: 244-250, 2013. [PubMed: 22686418] [Full Text: https://doi.org/10.1111/j.1399-0004.2012.01904.x]
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de The, H., Vivanco-Ruiz, M. M., Tiollais, P., Stunnenberg, H., Dejean, A. Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature 343: 177-180, 1990. [PubMed: 2153268] [Full Text: https://doi.org/10.1038/343177a0]
Dejean, A., Bougueleret, L., Grzeschik, K.-H., Tiollais, P. Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature 322: 70-72, 1986. [PubMed: 3014347] [Full Text: https://doi.org/10.1038/322070a0]
Koh, Y.-S., Moore, D. D. Linkage of the nuclear hormone receptor genes NR1D2, THRB, and RARB: evidence for an ancient, large-scale duplication. Genomics 57: 289-292, 1999. [PubMed: 10198169] [Full Text: https://doi.org/10.1006/geno.1998.5683]
Krezel, W., Ghyselinck, N., Samad, T. A., Dupe, V., Kastner, P., Borrelli, E., Chambon, P. Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279: 863-867, 1998. [PubMed: 9452386] [Full Text: https://doi.org/10.1126/science.279.5352.863]
Lotan, R., Xu, X.-C., Lippman, S. M., Ro, J. Y., Lee, J. S., Lee, J. J., Hong, W. K. Suppression of retinoic acid receptor-beta in premalignant oral lesions and its up-regulation by isotretinoin. New Eng. J. Med. 332: 1405-1410, 1995. [PubMed: 7723796] [Full Text: https://doi.org/10.1056/NEJM199505253322103]
Maret, S., Franken, P., Dauvilliers, Y., Ghyselinck, N. B., Chambon, P., Tafti, M. Retinoic acid signaling affects cortical synchrony during sleep. Science 310: 111-116, 2005. [PubMed: 16210540] [Full Text: https://doi.org/10.1126/science.1117623]
Mattei, M.-G., de The, H., Mattei, J.-F., Marchio, A., Tiollais, P., Dejean, A. Assignment of the human hap retinoic acid receptor RAR-beta gene to the p24 band of chromosome 3. Hum. Genet. 80: 189-190, 1988. [PubMed: 2844650] [Full Text: https://doi.org/10.1007/BF00702867]
Mattei, M.-G., Riviere, M., Krust, A., Ingvarsson, S., Vennstrom, B., Islam, M. Q., Levan, G., Kautner, P., Zelent, A., Chambon, P., Szpirer, J., Szpirer, C. Chromosomal assignment of retinoic acid receptor (RAR) genes in the human, mouse, and rat genomes. Genomics 10: 1061-1069, 1991. [PubMed: 1655630] [Full Text: https://doi.org/10.1016/0888-7543(91)90199-o]
Nadeau, J. H., Compton, J. G., Giguere, V., Rossant, J., Varmuza, S. Close linkage of retinoic acid receptor genes with homeobox- and keratin-encoding genes on paralogous segments of mouse chromosomes 11 and 15. Mammalian Genome 3: 202-208, 1992. [PubMed: 1377062] [Full Text: https://doi.org/10.1007/BF00355720]
Samad, A., Krezel, W., Chambon, P., Borrelli, E. Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family. Proc. Nat. Acad. Sci. 94: 14349-14354, 1997. [PubMed: 9405615] [Full Text: https://doi.org/10.1073/pnas.94.26.14349]
Srour, M., Chitayat, D., Caron, V., Chassaing, N., Bitoun, P., Patry, L., Cordier, M.-P., Capo-Chichi, J.-M., Francannet, C., Calvas, P., Ragge, N., Dobrzeniecka, S., Hamdan, F. F., Rouleau, G. A., Tremblay, A., Michaud, J. L. Recessive and dominant mutations in retinoic acid receptor beta in cases with microphthalmia and diaphragmatic hernia. Am. J. Hum. Genet. 93: 765-772, 2013. Note: Erratum: Am. J. Hum. Genet. 93: 994 only, 2013. [PubMed: 24075189] [Full Text: https://doi.org/10.1016/j.ajhg.2013.08.014]