* 180190

RETINOIC ACID RECEPTOR, GAMMA; RARG


Other entities represented in this entry:

RARG/NUP98 FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: RARG

Cytogenetic location: 12q13.13     Genomic coordinates (GRCh38): 12:53,210,569-53,232,209 (from NCBI)


TEXT

Description

Retinoic acid receptors (RARs), such as RARG, are nuclear hormone receptors that act as ligand-dependent transcriptional regulators. In their liganded state, RARs activate transcription, whereas in their nonliganded form, they repress transcription of their target genes. RARs have numerous target genes, which have retinoic response elements in their promoter regions (summary by Walkley et al., 2007).


Cloning and Expression

Rarg was first identified in mouse, where its RNA was detected predominantly in skin, a well-known target for retinoic acid. Krust et al. (1989) used mouse cDNA to clone the human counterpart. Comparisons of the amino acid sequences of all 6 human and mouse RARs indicated that the interspecies conservation of a given member of the RAR subfamily, i.e., alpha (RARA; 180240), beta (RARB; 180220), or gamma, is much higher than the conservation of all 3 receptors in a given species. These observations indicate that the 3 forms of retinoic acid receptor may perform specific functions. Krust et al. (1989) showed that RARG is the predominant RAR RNA species in human and mouse skin.

Ishikawa et al. (1990) gave a systematic comparison of the 3 RAR proteins and the thyroid receptor protein.


Mapping

According to unpublished observations of Mattei and Chambon cited by Ryseck et al. (1989), the RARG gene is located on chromosome 12q in the human and chromosome 15 in the mouse. By Southern analysis of somatic cell hybrid DNAs with a cDNA fragment, Ishikawa et al. (1990) confirmed the assignment to chromosome 12. By in situ hybridization, Mattei et al. (1991) localized the RARG gene to 12q13. They mapped the corresponding gene in the mouse to band F of chromosome 15. Using a panel of somatic cell hybrids that segregate rat chromosomes, they mapped the gene to chromosome 7 in that species.


Gene Function

Shimono et al. (2011) treated mouse mesenchymal stem cells with an RARG agonist and transplanted them into nude mice. Whereas control cells formed ectopic bone masses, cells that had been pretreated with the RARG agonist did not, suggesting that they had lost their skeletogenic potential. The cells became unresponsive to rBMP2 (112261) treatment in vitro, and showed decreases in phosphorylation of SMAD1 (601595), SMAD5 (603110), and SMAD8 (603295), and in overall levels of SMAD proteins.


Cytogenetics

Such et al. (2011) identified a NUP98 (601021)/RARG fusion gene resulting from a t(11;12)(p15;p13) translocation in bone marrow cells derived from a 35-year-old man with AML that had morphologic and immunophenotypic features of the hypergranular subtype of acute promyelocytic leukemia (APL; 612376). Sequence analysis determined that NUP98 exon 12 was fused in-frame to RARG exon 4, predicted to encode an 862-residue protein with aberrant RARG receptor function. The patient was treated with standard chemotherapy and bone marrow transplantation; response to ATRA was not assessed.


Animal Model

Walkley et al. (2007) found that 8-week-old Rarg -/- mice showed a growth defect, splenomegaly, and myeloproliferative disease, with significantly increased granulocyte/macrophage progenitors and granulocytes in bone marrow, peripheral blood, and spleen. The small number of Rarg -/- mice that survived to 12 months of age showed more pronounced myeloproliferative disease than younger Rarg -/- mice. Extramedullary hematopoiesis was observed in liver and adipose of older Rarg -/- mice, but none developed leukemia or lymphoma. Transplant studies revealed that the myeloproliferative disease was not intrinsic to hematopoietic cells and was due, at least in part, to significantly elevated Tnf-alpha (TNF; 191160) levels in Rarg -/- mice.

Shimono et al. (2011) studied transgenic mice expressing the Alk2 (102576) mutation Q207D, a constitutively active form of the receptor that is related to the ALK2 R206H mutation (102576.0001) that causes fibrodysplasia ossificans progressiva (FOP; 135100). Heterotopic ossification was essentially prevented in the mutant mice treated with the RARG agonist CD1530, compared to massive heterotopic ossification that developed in control mice.


REFERENCES

  1. Ishikawa, T., Umesono, K., Mangelsdorf, D. J., Aburatani, H., Stanger, B. Z., Shibasaki, Y., Imawari, M., Evans, R. M., Takaku, F. A functional retinoic acid receptor encoded by the gene on human chromosome 12. Molec. Endocr. 4: 837-844, 1990. [PubMed: 2172793, related citations] [Full Text]

  2. Krust, A., Kastner, P., Petkovich, M., Zelent, A., Chambon, P. A third human retinoic acid receptor, hRAR-gamma. Proc. Nat. Acad. Sci. 86: 5310-5314, 1989. [PubMed: 2546152, related citations] [Full Text]

  3. 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, related citations] [Full Text]

  4. Ryseck, R.-P., Macdonald-Bravo, H., Mattei, M. G., Siegfried, R. L., Bravo, R. Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. EMBO J. 8: 3327-3335, 1989. [PubMed: 2555161, related citations] [Full Text]

  5. Shimono, K., Tung, W., Macolino, C., Chi, A. H.-T., Didizian, J. H., Mundy, C., Chandraratna, R. A., Mishina, Y., Enomoto-Iwamoto, M., Pacifici, M., Iwamoto, M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nature Med. 17: 454-460, 2011. Note: Erratum: Nature Med. 18: 1592 only, 2010. [PubMed: 21460849, images, related citations] [Full Text]

  6. Such, E., Cervera, J., Valencia, A., Barragan, E., Ibanez, M., Luna, I., Fuster, O., Perez-Sirvent, M. L., Senent, L., Sempere, A., Martinez, J., Martin-Aragones, G., Sanz, M. A. A novel NUPR98/RARG gene fusion in acute myeloid leukemia resembling acute promyelocytic leukemia. Blood 117: 242-245, 2011. [PubMed: 20935257, related citations] [Full Text]

  7. Walkley, C. R., Olsen, G. H., Dworkin, S., Fabb, S. A., Swann, J., McArthur, G. A., Westmoreland, S. V., Chambon, P., Scadden, D. T., Purton, L. E. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma-deficiency. Cell 129: 1097-1110, 2007. [PubMed: 17574023, images, related citations] [Full Text]


Cassandra L. Kniffin - updated : 11/17/2011
Marla J. F. O'Neill - updated : 9/13/2011
Matthew B. Gross - updated : 10/13/2010
Patricia A. Hartz - updated : 10/13/2010
Creation Date:
Victor A. McKusick : 8/15/1989
tpirozzi : 10/01/2013
carol : 11/22/2011
ckniffin : 11/17/2011
carol : 9/14/2011
terry : 9/13/2011
mgross : 10/13/2010
mgross : 10/13/2010
terry : 10/13/2010
supermim : 3/16/1992
carol : 8/9/1991
carol : 2/4/1991
carol : 9/7/1990
supermim : 3/20/1990
supermim : 3/9/1990

* 180190

RETINOIC ACID RECEPTOR, GAMMA; RARG


Other entities represented in this entry:

RARG/NUP98 FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: RARG

Cytogenetic location: 12q13.13     Genomic coordinates (GRCh38): 12:53,210,569-53,232,209 (from NCBI)


TEXT

Description

Retinoic acid receptors (RARs), such as RARG, are nuclear hormone receptors that act as ligand-dependent transcriptional regulators. In their liganded state, RARs activate transcription, whereas in their nonliganded form, they repress transcription of their target genes. RARs have numerous target genes, which have retinoic response elements in their promoter regions (summary by Walkley et al., 2007).


Cloning and Expression

Rarg was first identified in mouse, where its RNA was detected predominantly in skin, a well-known target for retinoic acid. Krust et al. (1989) used mouse cDNA to clone the human counterpart. Comparisons of the amino acid sequences of all 6 human and mouse RARs indicated that the interspecies conservation of a given member of the RAR subfamily, i.e., alpha (RARA; 180240), beta (RARB; 180220), or gamma, is much higher than the conservation of all 3 receptors in a given species. These observations indicate that the 3 forms of retinoic acid receptor may perform specific functions. Krust et al. (1989) showed that RARG is the predominant RAR RNA species in human and mouse skin.

Ishikawa et al. (1990) gave a systematic comparison of the 3 RAR proteins and the thyroid receptor protein.


Mapping

According to unpublished observations of Mattei and Chambon cited by Ryseck et al. (1989), the RARG gene is located on chromosome 12q in the human and chromosome 15 in the mouse. By Southern analysis of somatic cell hybrid DNAs with a cDNA fragment, Ishikawa et al. (1990) confirmed the assignment to chromosome 12. By in situ hybridization, Mattei et al. (1991) localized the RARG gene to 12q13. They mapped the corresponding gene in the mouse to band F of chromosome 15. Using a panel of somatic cell hybrids that segregate rat chromosomes, they mapped the gene to chromosome 7 in that species.


Gene Function

Shimono et al. (2011) treated mouse mesenchymal stem cells with an RARG agonist and transplanted them into nude mice. Whereas control cells formed ectopic bone masses, cells that had been pretreated with the RARG agonist did not, suggesting that they had lost their skeletogenic potential. The cells became unresponsive to rBMP2 (112261) treatment in vitro, and showed decreases in phosphorylation of SMAD1 (601595), SMAD5 (603110), and SMAD8 (603295), and in overall levels of SMAD proteins.


Cytogenetics

Such et al. (2011) identified a NUP98 (601021)/RARG fusion gene resulting from a t(11;12)(p15;p13) translocation in bone marrow cells derived from a 35-year-old man with AML that had morphologic and immunophenotypic features of the hypergranular subtype of acute promyelocytic leukemia (APL; 612376). Sequence analysis determined that NUP98 exon 12 was fused in-frame to RARG exon 4, predicted to encode an 862-residue protein with aberrant RARG receptor function. The patient was treated with standard chemotherapy and bone marrow transplantation; response to ATRA was not assessed.


Animal Model

Walkley et al. (2007) found that 8-week-old Rarg -/- mice showed a growth defect, splenomegaly, and myeloproliferative disease, with significantly increased granulocyte/macrophage progenitors and granulocytes in bone marrow, peripheral blood, and spleen. The small number of Rarg -/- mice that survived to 12 months of age showed more pronounced myeloproliferative disease than younger Rarg -/- mice. Extramedullary hematopoiesis was observed in liver and adipose of older Rarg -/- mice, but none developed leukemia or lymphoma. Transplant studies revealed that the myeloproliferative disease was not intrinsic to hematopoietic cells and was due, at least in part, to significantly elevated Tnf-alpha (TNF; 191160) levels in Rarg -/- mice.

Shimono et al. (2011) studied transgenic mice expressing the Alk2 (102576) mutation Q207D, a constitutively active form of the receptor that is related to the ALK2 R206H mutation (102576.0001) that causes fibrodysplasia ossificans progressiva (FOP; 135100). Heterotopic ossification was essentially prevented in the mutant mice treated with the RARG agonist CD1530, compared to massive heterotopic ossification that developed in control mice.


REFERENCES

  1. Ishikawa, T., Umesono, K., Mangelsdorf, D. J., Aburatani, H., Stanger, B. Z., Shibasaki, Y., Imawari, M., Evans, R. M., Takaku, F. A functional retinoic acid receptor encoded by the gene on human chromosome 12. Molec. Endocr. 4: 837-844, 1990. [PubMed: 2172793] [Full Text: https://doi.org/10.1210/mend-4-6-837]

  2. Krust, A., Kastner, P., Petkovich, M., Zelent, A., Chambon, P. A third human retinoic acid receptor, hRAR-gamma. Proc. Nat. Acad. Sci. 86: 5310-5314, 1989. [PubMed: 2546152] [Full Text: https://doi.org/10.1073/pnas.86.14.5310]

  3. 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]

  4. Ryseck, R.-P., Macdonald-Bravo, H., Mattei, M. G., Siegfried, R. L., Bravo, R. Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. EMBO J. 8: 3327-3335, 1989. [PubMed: 2555161] [Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb08494.x]

  5. Shimono, K., Tung, W., Macolino, C., Chi, A. H.-T., Didizian, J. H., Mundy, C., Chandraratna, R. A., Mishina, Y., Enomoto-Iwamoto, M., Pacifici, M., Iwamoto, M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nature Med. 17: 454-460, 2011. Note: Erratum: Nature Med. 18: 1592 only, 2010. [PubMed: 21460849] [Full Text: https://doi.org/10.1038/nm.2334]

  6. Such, E., Cervera, J., Valencia, A., Barragan, E., Ibanez, M., Luna, I., Fuster, O., Perez-Sirvent, M. L., Senent, L., Sempere, A., Martinez, J., Martin-Aragones, G., Sanz, M. A. A novel NUPR98/RARG gene fusion in acute myeloid leukemia resembling acute promyelocytic leukemia. Blood 117: 242-245, 2011. [PubMed: 20935257] [Full Text: https://doi.org/10.1182/blood-2010-06-291658]

  7. Walkley, C. R., Olsen, G. H., Dworkin, S., Fabb, S. A., Swann, J., McArthur, G. A., Westmoreland, S. V., Chambon, P., Scadden, D. T., Purton, L. E. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma-deficiency. Cell 129: 1097-1110, 2007. [PubMed: 17574023] [Full Text: https://doi.org/10.1016/j.cell.2007.05.014]


Contributors:
Cassandra L. Kniffin - updated : 11/17/2011
Marla J. F. O'Neill - updated : 9/13/2011
Matthew B. Gross - updated : 10/13/2010
Patricia A. Hartz - updated : 10/13/2010

Creation Date:
Victor A. McKusick : 8/15/1989

Edit History:
tpirozzi : 10/01/2013
carol : 11/22/2011
ckniffin : 11/17/2011
carol : 9/14/2011
terry : 9/13/2011
mgross : 10/13/2010
mgross : 10/13/2010
terry : 10/13/2010
supermim : 3/16/1992
carol : 8/9/1991
carol : 2/4/1991
carol : 9/7/1990
supermim : 3/20/1990
supermim : 3/9/1990