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HGNC:2934 9p24.3 Entrez:1761 MIM.602424

Tuesday 20 April 2010

Definition: DMRT1 encodes a male-specific transcriptional regulator with a conserved zinc finger-like DNA-binding domain, the DM domain. DMRT1 is a key factor involved in sex determination and differentiation.

Heterozygous small deletions in 9p can cause complete and partial XY gonadal dysgenesis without other symptoms. Human DMRT1 gene, which is located at 9p24.3, is expressed in testis and ovary and has been considered, among others, a candidate autosomal gene responsible for gonadal dysgenesis.


- The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. (20007774)

- Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates.


- DMRT1-associated XY gonadal dysgenesis

  • A nucleotide insertion in DMRT1 3’UTR has been described in a patient of XY partial gonadal dygenesis. The 3’UTR+11insT is located within a conserved motif important for mRNA stabilization. (21340164)

- Variants near DMRT1 (as TERT and ATF7IP) are associated with testicular germ cell cancer. (Genome-wide association study / GWAS) (20543847)

Animal models

- Dmrt1 -/- mice

  • Raymond et al. (2000) found that adult male Dmrt1 -/- mice showed severe testis hypoplasia.
  • Microscopic and immunohistochemical examination revealed that Dmrt1 -/- seminiferous tubules were disorganized, Sertoli cells failed to differentiate, and germ cells were missing, apparently due to premeiotic germ cell death.
  • No ectopic ovarian tissue or Mullerian duct-derived structures were apparent in Dmrt1 -/- males.
  • In contrast, Dmrt1 +/- males had normal testis and were fertile, and Dmrt1 -/- females had normal ovaries and were fertile.

- Mice of the 129Sv strain, loss of Dmrt1 causes a high incidence of teratomas, whereas these tumors do not form in Dmrt1 mutant C57BL/6J mice. (20007774)

  • Conditional gene targeting indicates that Dmrt1 is required in fetal germ cells but not in Sertoli cells to prevent teratoma formation.
  • Mutant 129Sv germ cells undergo apparently normal differentiation up to embryonic day 13.5 (E13.5), but some cells fail to arrest mitosis and ectopically express pluripotency markers.
  • Expression analysis and chromatin immunoprecipitation identified DMRT1 target genes, whose missexpression may underlie teratoma formation.
  • DMRT1 indirectly activates the GDNF coreceptor Ret, and it directly represses the pluripotency regulator Sox2.
  • Analysis of human germ cell tumors reveals similar gene expression changes correlated to DMRT1 levels.
  • Dmrt1 behaves genetically as a dose-sensitive tumor suppressor gene in 129Sv mice, and natural variation in Dmrt1 activity can confer teratoma susceptibility.
  • There is a genetic link between testicular dysgenesis, pluripotency regulation, and teratoma susceptibility that is highly sensitive to genetic background and to gene dosage.

See also

- XY gonadal dysgenesis


- Novel DMRT1 3’UTR+11insT mutation associated to XY partial gonadal dysgenesis. Mello MP, Coeli FB, Assumpção JG, Castro TM, Maciel-Guerra AT, Marques-de-Faria AP, Baptista MT, Guerra-Júnior G. Arq Bras Endocrinol Metabol. 2010 Nov;54(8):749-53. PMID: 21340164 (Free)

- Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Turnbull C, Rapley EA, Seal S, Pernet D, Renwick A, Hughes D, Ricketts M, Linger R, Nsengimana J, Deloukas P, Huddart RA, Bishop DT, Easton DF, Stratton MR, Rahman N; UK Testicular Cancer Collaboration. Nat Genet. 2010 Jul;42(7):604-7. PMID: 20543847

- Genome-wide DNA methylation profiling reveals novel epigenetically regulated genes and non-coding RNAs in human testicular cancer. Cheung HH, Lee TL, Davis AJ, Taft DH, Rennert OM, Chan WY. Br J Cancer. 2010 Jan 19;102(2):419-27. PMID: 20051947

- The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Krentz AD, Murphy MW, Kim S, Cook MS, Capel B, Zhu R, Matin A, Sarver AL, Parker KL, Griswold MD, Looijenga LH, Bardwell VJ, Zarkower D. Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22323-8. PMID: 20007774 (Free)

- Raymond, C. S.; Murphy, M. W.; O’Sullivan, M. G.; Bardwell, V. J.; Zarkower, D. : Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev. 14: 2587-2595, 2000. PubMed ID : 11040213