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DMRT1  -  doublesex and mab-3 related transcription...

Homo sapiens

Synonyms: CT154, DM domain expressed in testis protein 1, DMT1, Doublesex-and mab-3-related transcription factor 1
 
 
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Disease relevance of DMRT1

  • We showed by fluorescence in situ hybridization analysis that both genes are deleted in the smallest reported sex-reversing 9p deletion, suggesting that gonadal dysgenesis in 9p-deleted individuals might be due to combined hemizygosity of DMRT1 and DMRT2 [1].
  • Findings in Patient 1 suggest that the phenotypic spectrum of the heterozygous DMRT deletion may include true hermaphroditism [2].
  • Based on the region of amplification defined on 9p and the associated expression plus confirmatory immunohistochemistry, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for involvement in the development of spermatocytic seminomas [3].
  • The facilitated transport of Fe by DMT1 at the blood-CSF barrier may partly contribute to Mn-induced neurodegenerative Parkinsonism [4].
  • We propose that DMT1(C1246T) (R416C) represents a complete loss-of-function, and that a quantitative reduction in DMT1 expression is the cause of the microcytic anemia and iron overload in the patient [5].
 

Psychiatry related information on DMRT1

  • A girl with mental retardation and multiple minor anomalies was found to have a complex chromosome 9p re-arrangement comprising a deleted, translocated Y chromosome, a deletion of the sex reversal gene region (DMRT1) at 9p, together with an inverted duplication of the more proximal part of 9p [6].
 

High impact information on DMRT1

  • We have identified a human gene, DMT1, that encodes a protein with a DM domain and find that DMT1 is expressed only in testis [7].
  • DMT1 maps to the distal short arm of chromosome 9, a location implicated in human XY sex reversal [7].
  • Two novel BCL6 translocation partner genes, 28S rRNA and DMRT1, and a new BCL6 translocation breakpoint in intron 2 were also identified [8].
  • DMT1 mutation: response of anemia to darbepoetin administration and implications for iron homeostasis [9].
  • However, differences in methylation pattern were found in the CpG islands flanking the DMRT1 gene, which is located at the 3' side of the ANKRD15 gene [10].
 

Chemical compound and disease context of DMRT1

 

Biological context of DMRT1

 

Anatomical context of DMRT1

 

Associations of DMRT1 with chemical compounds

  • Mammals have two genes (SRY and DMT1) for testis formation-androgenesis, an anti-testis gene, DAX1, an anti-Müllerian duct hormone, and steroid sex hormones [17].
  • Ebselen inhibited Fe(II) uptake (IC(50) of approximately 0.22 muM), but did not influence Fe(III) transport or DMT1-mediated manganese uptake [18].
  • These observations indicate that Fe(II) transport by DMT1 can be modulated by cellular redox status and suggest that ebselen may act therapeutically to limit iron-catalyzed damage due to transport inhibition [18].
  • An unrelated antioxidant, pyrrolidine dithiobarbamate (PDTC), also inhibited DMT1 activity (IC(50) of approximately 1.54 muM) [18].
  • DMT1 (divalent metal transporter 1) is a hydrogen-coupled divalent metal transporter with a substrate preference for iron, although the protein when expressed in frog oocytes transports a broad range of metals, including the toxic metals cadmium and lead [19].
 

Other interactions of DMRT1

  • Multispecies comparison was particularly effective for detecting CNGs, revealing several novel potential regulatory regions within DMRT3 and DMRT2 as well as DMRT1 [14].
  • Sequence analysis in cases 1-4 and 6 showed that they had normal sequences of each exon of DMRT1 and the DM domain of DMRT2 on the normal chromosome 9, and that cases 1-4 had normal SRY sequence [12].
  • Recently, the possibility of DMRT1 and/or DMRT2 (the genes for doublesex and mab-3 related transcription factor 1 and 2) being the sex determining genes(s) at 9p has been raised [2].
  • After stimulation with 50 nM phorbol 12-myristate 13-acetate (PMA), the cells differentiated into cells with mesenchymal characteristics and upregulated Dmrt-1 mRNA, possibly through the protein kinase C/mitogen-activated protein kinase/activated protein-1 signaling pathway [20].
 

Analytical, diagnostic and therapeutic context of DMRT1

References

  1. A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators. Raymond, C.S., Parker, E.D., Kettlewell, J.R., Brown, L.G., Page, D.C., Kusz, K., Jaruzelska, J., Reinberg, Y., Flejter, W.L., Bardwell, V.J., Hirsch, B., Zarkower, D. Hum. Mol. Genet. (1999) [Pubmed]
  2. Three patients with 9p deletions including DMRT1 and DMRT2: a girl with XY complement, bilateral ovotestes, and extreme growth retardation, and two XX females with normal pubertal development. Ounap, K., Uibo, O., Zordania, R., Kiho, L., Ilus, T., Oiglane-Shlik, E., Bartsch, O. Am. J. Med. Genet. A (2004) [Pubmed]
  3. Genomic and expression profiling of human spermatocytic seminomas: primary spermatocyte as tumorigenic precursor and DMRT1 as candidate chromosome 9 gene. Looijenga, L.H., Hersmus, R., Gillis, A.J., Pfundt, R., Stoop, H.J., van Gurp, R.J., Veltman, J., Beverloo, H.B., van Drunen, E., van Kessel, A.G., Pera, R.R., Schneider, D.T., Summersgill, B., Shipley, J., McIntyre, A., van der Spek, P., Schoenmakers, E., Oosterhuis, J.W. Cancer Res. (2006) [Pubmed]
  4. Upregulation of DMT1 expression in choroidal epithelia of the blood-CSF barrier following manganese exposure in vitro. Wang, X., Li, G.J., Zheng, W. Brain Res. (2006) [Pubmed]
  5. A novel R416C mutation in human DMT1 (SLC11A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload. Lam-Yuk-Tseung, S., Camaschella, C., Iolascon, A., Gros, P. Blood Cells Mol. Dis. (2006) [Pubmed]
  6. Complex chromosome re-arrangement 45,X,t(Y;9) in a girl with sex reversal and mental retardation. de Ravel, T.J., Fryns, J.P., Van Driessche, J., Vermeesch, J.R. Am. J. Med. Genet. A (2004) [Pubmed]
  7. Evidence for evolutionary conservation of sex-determining genes. Raymond, C.S., Shamu, C.E., Shen, M.M., Seifert, K.J., Hirsch, B., Hodgkin, J., Zarkower, D. Nature (1998) [Pubmed]
  8. High BCL6 expression predicts better prognosis, independent of BCL6 translocation status, translocation partner, or BCL6-deregulating mutations, in gastric lymphoma. Chen, Y.W., Hu, X.T., Liang, A.C., Au, W.Y., So, C.C., Wong, M.L., Shen, L., Tao, Q., Chu, K.M., Kwong, Y.L., Liang, R.H., Srivastava, G. Blood (2006) [Pubmed]
  9. DMT1 mutation: response of anemia to darbepoetin administration and implications for iron homeostasis. Pospisilova, D., Mims, M.P., Nemeth, E., Ganz, T., Prchal, J.T. Blood (2006) [Pubmed]
  10. Deletion of the ANKRD15 gene at 9p24.3 causes parent-of-origin-dependent inheritance of familial cerebral palsy. Lerer, I., Sagi, M., Meiner, V., Cohen, T., Zlotogora, J., Abeliovich, D. Hum. Mol. Genet. (2005) [Pubmed]
  11. Magnetic resonance tagging and echocardiographic response to dobutamine and functional improvement after reperfused myocardial infarction. Kramer, C.M., Malkowski, M.J., Mankad, S., Theobald, T.M., Pakstis, D.L., Rogers, W.J. Am. Heart J. (2002) [Pubmed]
  12. Sex-determining gene(s) on distal 9p: clinical and molecular studies in six cases. Muroya, K., Okuyama, T., Goishi, K., Ogiso, Y., Fukuda, S., Kameyama, J., Sato, H., Suzuki, Y., Terasaki, H., Gomyo, H., Wakui, K., Fukushima, Y., Ogata, T. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  13. The human doublesex-related gene, DMRT2, is homologous to a gene involved in somitogenesis and encodes a potential bicistronic transcript. Ottolenghi, C., Veitia, R., Barbieri, M., Fellous, M., McElreavey, K. Genomics (2000) [Pubmed]
  14. DMRT gene cluster analysis in the platypus: New insights into genomic organization and regulatory regions. El-Mogharbel, N., Wakefield, M., Deakin, J.E., Tsend-Ayush, E., Gr??tzner, F., Alsop, A., Ezaz, T., Marshall Graves, J.A. Genomics (2007) [Pubmed]
  15. Sex-specific expression of an evolutionarily conserved male regulatory gene, DMRT1, in birds. Shan, Z., Nanda, I., Wang, Y., Schmid, M., Vortkamp, A., Haaf, T. Cytogenet. Cell Genet. (2000) [Pubmed]
  16. Differential and spermatogenic cell-specific expression of DMRT1 during sex reversal in protogynous hermaphroditic groupers. Xia, W., Zhou, L., Yao, B., Li, C.J., Gui, J.F. Mol. Cell. Endocrinol. (2007) [Pubmed]
  17. "Insects do not have sex hormones": a myth? De Loof, A., Huybrechts, R. Gen. Comp. Endocrinol. (1998) [Pubmed]
  18. Small-Molecule Screening Identifies the Selanazal Drug Ebselen as a Potent Inhibitor of DMT1-Mediated Iron Uptake. Wetli, H.A., Buckett, P.D., Wessling-Resnick, M. Chem. Biol. (2006) [Pubmed]
  19. Effect of DMT1 knockdown on iron, cadmium, and lead uptake in Caco-2 cells. Bannon, D.I., Abounader, R., Lees, P.S., Bressler, J.P. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  20. DMRT-1 expression during NEC8 human embryonic carcinoma cell differentiation. Koji, H., Yamada, A., Nagasawa, T., Gamou, S. Cancer Sci. (2006) [Pubmed]
  21. Expression of Dmrt1 protein in developing and in sex-reversed gonads of amphibians. Aoyama, S., Shibata, K., Tokunaga, S., Takase, M., Matsui, K., Nakamura, M. Cytogenet. Genome Res. (2003) [Pubmed]
  22. Belgrade rats display liver iron loading. Thompson, K., Molina, R.M., Brain, J.D., Wessling-Resnick, M. J. Nutr. (2006) [Pubmed]
 
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