Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: RARA
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:40,309,180-40,357,643 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | Leukemia, acute promyelocytic | 612376 | 1 |
Retinoid signaling is transduced by 2 families of nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR; see 180245), which form RXR/RAR heterodimers. In the absence of ligand, DNA-bound RXR/RARA represses transcription by recruiting the corepressors NCOR1 (600849), SMRT (NCOR2; 600848), and histone deacetylase (see 601241). When ligand binds to the complex, it induces a conformational change allowing the recruitment of coactivators, histone acetyltransferases (see 603053), and the basic transcription machinery. Translocations that always involve rearrangement of the RARA gene are a cardinal feature of acute promyelocytic leukemia (APL; 612376). The most frequent translocation is t(15,17)(q21;q22), which fuses the RARA gene with the PML gene (102578) (Vitoux et al., 2007).
Petkovich et al. (1987) cloned a cDNA encoding a protein that bound retinoic acid with high affinity. The protein was found to be homologous to the receptors for steroid hormones, thyroid hormones, and vitamin D3, and appeared to be a retinoic acid-inducible transacting enhancer factor. Thus, the molecular mechanisms of the effect of vitamin A on embryonic development, differentiation and tumor cell growth may be similar to those described for other members of this nuclear receptor family. The genes for all the steroid/thyroid receptors show a common pattern of structure, with 4 regions: A/B, C, D, and E (Robertson, 1987). The function of region A/B is unknown; C encodes the DNA-binding domain; D is believed to be a hinge region; and E encodes the ligand-binding domain. In general, the DNA-binding domain is most highly conserved, both within and between the 2 groups of receptors (steroid and thyroid); the ligand-binding domains show less homology.
Hjalt and Murray (1999) determined that the RARA gene contains 9 exons, with the start codon in exon 2.
Arveiler et al. (1988) described a RFLP of the RAR gene. Bale et al. (1988) indicated that the RAR locus had been assigned to chromosome 17 by study of human-rodent somatic cell hybrids. Using a cDNA probe, Mattei et al. (1988) localized the RAR gene to 17q21 by in situ hybridization.
Brand et al. (1988) presented evidence for the existence of 2 retinoic acid receptors, RAR-alpha and RAR-beta (RARB; 180220), mapping to chromosome 17q21.1 and 3p24, respectively. The alpha and beta forms of RAR were found to be more homologous to the 2 closely related thyroid hormone receptors alpha (190120) and beta (190160), located on 17q11.2 and 3p25-p21, respectively, than to any other members of the nuclear receptor family. These observations suggest that the thyroid hormone and retinoic acid receptors evolved by gene, and possibly chromosome, duplications from a common ancestor, which itself diverged rather early in evolution from the common ancestor of the steroid receptor group of the family. They noted that the counterparts of the human RARA and RARB genes are present in both the mouse and chicken genomes. By genetic linkage studies using multiple DNA markers from the 17q12-q21 region, Anderson et al. (1993) placed the RARA gene on the genetic map of the region.
Mattei et al. (1991) mapped the RARA, RARB, and RARG (180190) genes in man, mouse, and rat, thereby establishing or confirming and extending the following homologies: (1) between human chromosome 17, mouse chromosome 11, and rat chromosome 10, as indicated by the location of RARA; (2) between human chromosome 3, mouse chromosome 14, and rat chromosome 15, as indicated by RARB; and (3) between human chromosome 12, mouse chromosome 15, and rat chromosome 7, as indicated by RARG. The various assignments also indicated the retention of tight linkage between RAR and HOX gene clusters. Nadeau et al. (1992) pointed out that, in the mouse, RARA is located on chromosome 11 near the homeobox-2 complex (see 142960) and the keratin type I complex (148080), whereas RARG is on mouse chromosome 15 near the homeobox-3 complex (see 142970) and the keratin type II complex (see 139350). The close proximity of these genes may be functionally significant but has evolutionary significance, at any rate, indicating the existence of homeologous segments of both in man and mouse.
McNamara et al. (2001) reported a hormone-dependent interaction of the nuclear receptors RARA and RXRA (180245) with CLOCK (601851) and MOP4 (603347). They found that these interactions negatively regulate CLOCK-BMAL1 (602550) and MOP4-BMAL1 heterodimer-mediated transcriptional activation of clock gene expression in vascular cells. MOP4 exhibited a robust rhythm in the vasculature, and retinoic acid could phase shift PER2 (603426) mRNA rhythmicity in vivo and in serum-induced smooth muscle cells in vitro, providing a molecular mechanism for hormonal control of clock gene expression. McNamara et al. (2001) proposed that circadian or periodic availability of nuclear hormones may play a critical role in resetting a peripheral vascular clock.
Germain et al. (2002) showed that RXR can bind ligand and recruit coactivators as a heterodimer with apo-retinoic acid receptor (apo-RAR). However, in the usual cellular environment corepressors do not dissociate and they prohibit coactivator access because coregulator binding is mutually exclusive.
Epping et al. (2005) identified PRAME (606021) as a dominant repressor of retinoic acid receptor signaling. PRAME bound to RARA in the presence of retinoic acid, preventing receptor activation, and PRAME expression conferred resistance to retinoic acid-induced proliferation arrest, differentiation, and apoptosis. Knockdown of PRAME in melanoma (155600) cells using siRNA restored RAR signaling and reinstated sensitivity to the antiproliferative effects of retinoic acid in vitro and in vivo. Epping et al. (2005) noted that PRAME is overexpressed in a variety of cancers, and likely confers growth or survival advantages in these cells by antagonizing RAR signaling.
Moon et al. (2012) showed that CAC1 (CACUL1; 618764) and RAR-alpha interacted in a ligand-independent manner and colocalized to nucleus in transacted H1299 cells. Interaction with CAC1 suppressed RAR-alpha transcriptional activity, and CoRNR box-2 of CAC1 was required for both RAR-alpha binding and repression. Furthermore, CAC1 interacted and cooperated with HDACs, especially HDAC2 (605164), in suppression of RAR-alpha activity. CAC1 negatively regulated retinoic acid-induced neuronal differentiation, as knockdown of CAC1 in P19 cells sensitized them to neuronal differentiation by increasing RAR-alpha activation.
Sugrue et al. (2019) found that mouse Hectd1 (618649) interacted with Rara and influenced its ubiquitination. Hectd1-deficient mice had abnormal aortic arch development due to reduced retinoic acid signaling.
RARA Fusion Proteins
For information on the generation of RARA fusion genes through translocations associated with acute promyelocytic leukemia (APL), see CYTOGENETICS.
Chen et al. (1994) cloned cDNAs encoding PLZF (176797)-RARA chimeric proteins and studied their transactivating activities. A 'dominant-negative' effect was observed when PLZF-RARA fusion proteins were cotransfected with vectors expressing RARA and RXRA. These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicated the fusion proteins in the molecular pathogenesis of APL.
Fusion of PML (102578) and TIF1A (603406) to RARA and BRAF (164757), respectively, results in the production of PML-RAR-alpha and TIF1-alpha-B-RAF (T18) oncoproteins. Zhong et al. (1999) showed that PML, TIF1-alpha, and RXR-alpha (180245)/RAR-alpha function together in a retinoic acid-dependent transcription complex. They found that PML acts as a ligand-dependent coactivator of RXR-alpha/RARA-alpha. T18, similar to PML-RAR-alpha, disrupts the retinoic acid-dependent activity of this complex in a dominant-negative manner, resulting in a growth advantage. PML-RAR-alpha was the first example of an oncoprotein generated by the fusion of 2 molecules participating in the same pathway, specifically the fusion of a transcription factor to one of its own cofactors. Since the PML and RAR-alpha pathways converge at the transcriptional level, there is no need for a double-dominant-negative product to explain the pathogenesis of APL.
Grignani et al. (1998) demonstrated that both PML-RAR-alpha and PLZF-RAR-alpha fusion proteins recruit the nuclear corepressor (NCOR; see 600849)-histone deacetylase (see 601241) complex through the RAR-alpha CoR box. PLZF-RAR-alpha contains a second, retinoic acid-resistant binding site in the PLZF amino-terminal region. High doses of retinoic acid release histone deacetylase activity from PML-RAR-alpha, but not from PLZF-RAR-alpha. Mutation of the NCOR binding site abolishes the ability of PML-RAR-alpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biologic effects of PLZF-RAR-alpha from being an inhibitor to an activator of the retinoic acid signaling pathway. Therefore, Grignani et al. (1998) concluded that recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of retinoic acid on the stability of the PML-RAR-alpha and PLZF-RAR-alpha corepressor complexes determines the differential response of APLs to retinoic acid.
RAR and acute myeloid leukemia-1 (AML1; 151385) transcription factors are found in leukemias as fusion proteins with PML and ETO (CBFA2T1; 133435), respectively. Association of PML-RAR and AML1-ETO with the NCOR-histone deacetylase complex is required to block hematopoietic differentiation. Minucci et al. (2000) showed that PML-RAR and AML1-ETO exist in vivo within high molecular weight nuclear complexes, reflecting their oligomeric state. Oligomerization requires PML or ETO coiled-coil regions and is responsible for abnormal recruitment of NCOR, transcriptional repression, and impaired differentiation of primary hematopoietic precursors. Fusion of RAR to a heterologous oligomerization domain recapitulated the properties of PML-RAR, indicating that oligomerization per se is sufficient to achieve transforming potential. These results showed that oligomerization of a transcription factor, imposing an altered interaction with transcriptional coregulators, represents a novel mechanism of oncogenic activation.
The recruitment of the nuclear receptor corepressor SMRT (NCOR2; 600848) and subsequent repression of retinoid target genes is critical for the oncogenic function of PML-RARA. Lin and Evans (2000) showed that the ability of PML-RARA to form homodimers is both necessary and sufficient for its increased binding efficiency to corepressor and its inhibitory effects on hormonal responses in myeloid differentiation. Furthermore, the authors found that altered stoichiometric interaction of SMRT with PML-RARA homodimers may underlie these processes. An RXR mutant lacking transactivation function AF2 recapitulated many biochemical and functional properties of PML-RARA. Taken together, these results indicated that altered dimerization of a transcription factor can be directly linked to cellular transformation and implicated dimerization interfaces of oncogenes as potential drug targets.
Lin et al. (1998) reported that the association of PLZF-RAR-alpha and PML-RAR-alpha with the histone deacetylase complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of retinoic acid-sensitive, and restore retinoid responses of retinoic acid-resistant, APL cell lines. Lin et al. (1998) concluded that oncogenic retinoic acid receptors mediate leukemogenesis through aberrant chromatin acetylation, and that pharmacologic manipulation of nuclear receptor cofactors may be a useful approach in the treatment of human disease.
Pandolfi (2001) reviewed the roles of the RAR-alpha and PML genes in the pathogenesis of APL.
Zelent et al. (2001) reviewed the functions of the proteins encoded by the different RAR-alpha partner genes found in association with acute promyelocytic leukemia, and the implications that these may have for the molecular pathogenesis of APL. The 5 genes reviewed were PML (102578), PLZF (176797), NPM (164040), NUMA1 (164009), and STAT5B (604260).
The fusion protein PML-RARA initiates APL when expressed in the early myeloid compartment of transgenic mice. Lane and Ley (2003) found that PML-RARA was cleaved in several positions by a neutral serine protease in a human myeloid cell line; purification revealed that the protease was neutrophil elastase (ELA2; 130130). Immunofluorescence localization studies suggested that cleavage of PML-RARA must have occurred within the cell, perhaps within the nucleus. The functional importance of ELA2 for APL development was assessed in Ela2-deficient mice. More than 90% of bone marrow PML-RARA-cleaving activity was lost in the absence of Ela2, and Ela2-deficient animals, but not cathepsin G (116830)-deficient animals, were protected from APL development. The authors determined that primary mouse and human APL cells also contained ELA2-dependent PML-RARA-cleaving activity. Lane and Ley (2003) concluded that, since ELA2 is maximally produced in promyelocytes, it may play a role in APL pathogenesis by facilitating the leukemogenic potential of PML-RARA.
Villa et al. (2006) found that MBD1 (156535) cooperated with PML-RARA in transcriptional repression and cellular transformation in human cell lines. PML-RARA recruited MBD1 to its target promoter through an HDAC3 (605166)-mediated mechanism. Binding of HDAC3 and MBD1 was not confined to the target promoter, but was instead spread over the locus. Knockdown of HDAC3 expression by RNA interference in acute promyelocytic leukemia cells alleviated PML-RARA-induced promoter silencing. Furthermore, retroviral expression of dominant-negative mutants of MBD1 in human hematopoietic precursors interfered with PML-RARA-induced repression and restored cell differentiation. Villa et al. (2006) concluded that PML-RARA recruits an HDAC3-MBD1 complex to target promoters to establish and maintain chromatin silencing.
Guidez et al. (2007) identified CRABP1 (180230) as a target of both PLZF and the RARA/PLZF fusion protein. PLZF repressed CRABP1 through propagation of chromatin condensation from a remote intronic binding element, culminating in silencing of the CRABP1 promoter. Although the canonical PLZF/RARA oncoprotein had no effect on PLZF-mediated repression, the reciprocal translocation product, RARA/PLZF, bound to this remote binding site, recruited p300 (EP300; 602700), and induced promoter hypomethylation and CRABP1 upregulation. Similarly, retinoic acid-resistant murine blasts that expressed both fusion proteins expressed much higher levels of Crabp1 than retinoic acid-sensitive cells expressing Plzf/Rara alone. RARA/PLZF conferred retinoic acid resistance to a retinoid-sensitive acute myeloid leukemia cell line in a CRABP1-dependent fashion. Guidez et al. (2007) concluded that upregulation of CRABP1 by RARA/PLZF contributes to retinoid resistance in leukemia.
RARA/PML Fusion Gene
Acute promyelocytic leukemia (APL), known as acute myeloid leukemia-3, AML3, or M3 in the French-American-British (FAB) classification, is characterized by a predominance of malignant promyelocytes that carry a reciprocal translocation between the long arms of chromosomes 15 and 17: t(15;17)(q22;q11.2-q12). This translocation is diagnostic for APL, as it is present in almost 100% of cases. Borrow et al. (1990) used a NotI linking clone to detect this translocation on pulsed field gel electrophoresis and subsequently with conventional Southern analysis. The breakpoints in 10 APL cases examined were shown to cluster in a 12-kb region of chromosome 17, which contained 2 CpG-rich islands. A comparison of the sequence of cDNA clones from the region of the breakpoint was compared with the EMBL database revealed that the cDNA was that of RARA, which maps to 17q21.1, distal to the APL breakpoint region. They concluded that the cDNAs lay outside the 12-kb breakpoint region and that all of the 15q+ APL breakpoints lie in the first intron of RARA. Since RARA is interrupted in an intron, it is most likely that the product of the translocation is a fusion protein. Borrow et al. (1990) suggested that the chimeric fusion protein encoded by the 15q+ derivative would retain the DNA- and ligand-binding domains of RARA, whereas the transcription-activating function of the 5-prime end of RARA would be replaced with a novel N-terminus, potentially changing the profile of genes activated. The involvement of RARA at the APL breakpoint may explain why the use of retinoic acid as a therapeutic differentiation agent in the treatment of acute myeloid leukemias is limited to APL. Lemons et al. (1990) also cloned the APL breakpoint region.
Because RARA maps close to the breakpoint of the t(15;17) translocation specifically associated with acute promyelocytic leukemia, and because retinoic acid has the ability to induce in vivo differentiation of APL cells into mature granulocytes, de The et al. (1990) analyzed the RARA gene structure and expression in APL cells. In one APL-derived cell line, they found that the RARA gene had been translocated to a locus, MYL (PML; 102578), on chromosome 15, resulting in the synthesis of an MYL/RARA fusion mRNA. (PML later became the preferred designation for the chromosome 15 gene that contributed to the chimeric gene product.) Using 2 probes located on either side of the cloned breakpoint, they found genomic rearrangements of one or the other locus in 6 of 8 patients, demonstrating that the RARA and/or MYL genes are frequently rearranged in APL and that the breakpoints are clustered. The findings strongly implicated RARA in leukemogenesis.
Alcalay et al. (1991) likewise demonstrated that the chromosome 17 breakpoint in APL lies within the RARA locus. The translocation site occurred in the 3-prime end of the RARA intron 1, 370 bp upstream from the splicing donor site of exon 2, and separated the first coding exon (exon 1) from the rest of the gene. By in situ hybridization, they mapped a probe from the translocation site to normal 15q23-q24, which is more distal than the site determined by others for either the chromosome 17 break in APL or the location of the normal RARA gene.
Hiorns et al. (1994) showed that APL patients with cytogenetically normal chromosomes 15 and 17 may nevertheless have involvement of both PML and RARA genes. Thus there is a subgroup of APL, t(15;17)-negative/PML-RARA-positive, that is analogous to Philadelphia chromosome-negative/BCR-ABL-positive chronic myelogenous leukemia (CML; 608232). The amount of chromosome 17 material inserted into chromosome 15 in the case studied by Hiorns et al. (1994) was too small to be detected cytogenetically. In cases of Philadelphia chromosome-negative/BCR-ABL-positive CML, the amount of DNA transferred can be substantial (Rassool et al., 1990).
RARA/PLZF Fusion Gene
Almost all patients with APL have a chromosomal translocation t(15;17)(q22;q21). Molecular studies reveal that the translocation results in a chimeric gene through fusion between the PML gene on chromosome 15 and the RARA gene on chromosome 17 (Chen et al., 1993). Chen et al. (1993) reported studies of a Chinese patient with APL and a variant translocation t(11;17)(q23;21) in which a gene on 11q23.1, designated PLZF (176797), was fused to the RARA gene on chromosome 17. Fluorescence in situ hybridization using a PLZF-specific probe localized the PLZF gene to chromosome 11q23.1. Similar to t(15;17) APL, all-trans retinoic acid treatment produced an early leukocytosis that was followed by a myeloid maturation, but the patient died too early to achieve remission.
RARA/NUMA1 Fusion Gene
See Wells et al. (1997) and NUMA1 (164009) for discussion of a RAR-NUMA1 fusion gene associated with APL.
RARA/PRKAR1A Fusion Gene
Catalano et al. (2007) reported a 66-year-old man with APL but without the classic t(15;17) translocation. FISH and RT-PCR studies identified a RARA/PRKAR1A fusion gene, possibly resulting from an insertion of RARA distal to PRKAR1A on chromosome 17q24, followed by a deletion of 3-prime PRKAR1A, 5-prime RARA, and any intervening sequences. The fusion transcript resulted from cryptic splicing of the first 100 bases of PRKAR1A exon 3 to RARA exon 3, and predicted a 495-amino acid fusion protein. The C-terminal end of RARA involved is that shared by all RARA rearrangements in APL. The patient had a good response to chemotherapy with complete remission of the disease by 11 months.
Cheng et al. (1999) generated transgenic mice with PLZF-RARA and NPM (164040)-RARA. PLZF-RARA transgenic animals developed chronic myeloid leukemia (CML; 608232)-like phenotypes at an early stage in life (within 3 months in 5 of 6 mice), whereas 3 NPM-RARA transgenic mice showed a spectrum of phenotypes from typical APL to CML relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZF-RARA transgenic mice, those from NPM-RARA transgenic mice could be induced to differentiate by all-trans retinoic acid (ATRA). Cheng et al. (1999) found that in interacting with nuclear coreceptors the 2 fusion proteins had different ligand sensitivities, which may be the underlying molecular mechanism for differential responses to ATRA. These data clearly established the leukemogenic role of PLZF-RARA and NPM-RARA and the importance of fusion receptor/corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.
He et al. (2000) generated transgenic mice expressing RARA-PLZF and PLZF-RARA in their promyelocytes. RARA-PLZF transgenic mice did not develop leukemia. However, PLZF-RARA/RARA-PLZF double transgenic mice developed leukemia with classic APL features. The authors demonstrated that RARA-PLZF can interfere with PLZF transcriptional repression, and that this is critical for APL pathogenesis, since leukemias in PLZF-deficient/PLZF-RARA mutants and in PLZF-RARA/RARA-PLZF transgenic mice were indistinguishable. Thus, both products of a cancer-associated translocation are crucial in determining the distinctive features of the disease.
In an animal model of acute promyelocytic leukemia, Padua et al. (2003) developed a DNA-based vaccine by fusing the human PML-RARA oncogene to tetanus fragment C (FrC) sequences. Padua et al. (2003) showed for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and in combination with ATRA. The survival advantage was concomitant with time-dependent antibody production and an increase in interferon-gamma (IFNG; 147570). Padua et al. (2003) also showed that ATRA therapy on its own triggered an immune response in this model. When DNA vaccination and conventional ATRA therapy were combined, they induced protective immune responses against leukemia progression in mice. Padua et al. (2003) concluded that this may provide a new approach to improve clinical outcome in human leukemia.
Keegan et al. (2005) presented a new mechanism for regulating the number of progenitor cells in organ development by limiting their density within a competent region. Using a zebrafish mutation that disrupts function of raldh2 (603687), they demonstrated that retinoic acid signaling restricted cardiac specification in the zebrafish embryo. Reduction of retinoic acid signaling caused formation of an excess of cardiomyocytes, via fate transformations that increased cardiac progenitor density within a multipotential zone. Thus, retinoic acid signaling creates a balance between cardiac and noncardiac identities, thereby refining the dimensions of the cardiac progenitor pool.
The report of Fujiki et al. (2009), which found that nuclear GlcNAcylation of a histone lysine methyltransferase (HKMT), MLL5 (608444), by O-GlcNAc transferase (300255) facilitates retinoic acid-induced granulopoiesis in human HL60 promyelocytes through methylation of H3K4, was retracted.
Associations Pending Confirmation
For discussion of a possible association between syndromic chorioretinal coloboma and variation in the RARA gene, see 180240.0001.
This variant is classified as a variant of unknown significance because its contribution to syndromic chorioretinal coloboma has not been confirmed.
Jakubiuk-Tomaszuk et al. (2019) reported a 7-year-old Polish girl with right iris and chorioretinal coloboma, developmental delay and muscular hypotonia, dilated pulmonary artery, and ectopic kidney, who was heterozygous for a de novo c.826C-T transition (c.826C-T, NM_000964) in the RARA gene, resulting in an arg276-to-trp (R276W) substitution at a residue known to be important for binding of retinoic acid. The mutation was not found in her unaffected parents or 2 unaffected brothers, in an in-house database of more than 2,000 Polish DNA samples, or in the gnomAD database. Other medical problems in the proband included poor weight gain, ankyloglossia, and gastroesophageal reflux. Examination at age 7 years showed short stature, thoracic hyperkyphosis, and rounded shoulders. She exhibited minor dysmorphic features, including arched eyebrows, broad nasal root, full cheeks, protruding ears, and sandal gap. Ultrasonography showed enlarged pulmonary trunk, accessory spleen, and ectopic left kidney. Brain MRI revealed asymmetric and slightly enlarged lateral ventricles, pineal gland cysts, and a posterior fossa arachnoid cyst. Ophthalmologic examination showed right iris coloboma and left iris hyperpigmentation, right chorioretinal coloboma with peripapillary atrophy, severe amblyopia, bilateral myopia with astigmatism, and bilateral optic nerve head drusen. Best corrected visual acuity was 20/65 on the right and 20/20 on the right. Optical coherence tomography revealed slight retinoschisis in the inner and outer nuclear layers of the retina near the borders of the chorioretinal coloboma below the macula in the right eye, and both optic discs were slightly elevated due to optic disc nerve head drusen. The proband attended a regular school and had well-developed fine motor skills, but continued to have impairment of gross motor skills, which the authors suggested might be related to her muscular hypotonia.
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