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Gene Review

SRY  -  sex determining region Y

Homo sapiens

Synonyms: SRXX1, SRXY1, Sex-determining region Y protein, TDF, TDY, ...
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Disease relevance of SRY


Psychiatry related information on SRY

  • OBJECTIVE: To evaluate the safety and efficacy of once daily doses of tenofovir DF (TDF) administered in combination with other antiretroviral therapy (ART) in treatment-experienced HIV-1-infected patients with incomplete virological suppression [4].
  • There were significant increases in heat pain threshold for TDF 25mug/h and TDB 35mug/h. Painful electrical stimulation failed to demonstrate an analgesic effect [5].

High impact information on SRY

  • These differences begin to unfold during fetal development, when the Y-chromosomal Sry ("sex-determining region Y") gene is activated in males and acts as a switch that diverts the fate of the undifferentiated gonadal primordia, the genital ridges, towards testis development [6].
  • Mammalian sex determination is governed by the presence of the sex determining region Y gene (SRY) on the Y chromosome [7].
  • Mutations in the human SRY-related gene, SOX9, located on chromosome 17, have recently been associated with the sex reversal and skeletal dysmorphology syndrome, campomelic dysplasia [8].
  • These data indicate that, in addition to a role in testis determination, SRY may have other functions [corrected] [9].
  • We show the marsupial SRY gene cannot be exclusively coupled to Sertoli cell differentiation, as this gene is expressed in the male fetus from several days before genital ridge formation until 40 days after birth [9].

Chemical compound and disease context of SRY

  • In this report we describe the clinical, endocrinological and molecular data of a patient with complete 46,XY gonadal dysgenesis caused by a de novo mutation affecting SRY amino acid phenylalanine at position 67 (F67L), located within the highly conserved high mobility group (HMG) box coding region of the gene [10].
  • TDF is selectively inactivated during protein synthesis inhibition by cycloheximide and at a late stage of adenovirus infection, thus accounting for the loss of RNA Pol III-mediated transcription of the tRNA and VA RNA genes under these conditions [11].
  • BACKGROUND: Tenofovir (TDF) is an adenosine nucleotide analogue that has been approved for the treatment of HIV-1 infection [12].
  • Presence of M184V mutation was related with a greater reduction in HIV RNA during d4T/TDF exposure [13].
  • The combination of didanosine (ddI) and tenofovir (TDF) has potential advantages, but because of several pitfalls (unexpected decreases in CD4+ T cells, increased risk of pancreatitis) its use has been questioned [14].

Biological context of SRY


Anatomical context of SRY

  • Functional studies of SRY in a cell line from embryonic gonadal ridge demonstrated activation of a gene-regulatory pathway leading to expression of MIS [18].
  • Analysis of lymphocyte DNA from the respective fathers revealed that they carry both the wild-type and the mutant version of the SRY gene [19].
  • The SRY gene of five subjects with 46,XY complete gonadal dysgenesis (46,XY karyotype, completely female external genitalia, normal Müllerian ducts, and streak gonads) was evaluated for possible mutations in the coding region by using both single-strand conformation polymorphism (SSCP) assay and DNA sequencing [20].
  • In order to identify genetic defects associated with subjects with the disease, we performed molecular analyses of the SRY gene in DNA from blood leukocytes and gonadal tissue in 12 true hermaphrodites with different karyotypes [21].
  • By immunohistochemistry SRY protein was detected in all ovotestes, predominantly in Sertoli and germ cells [22].

Associations of SRY with chemical compounds

  • Finally, these data demonstrated that NPCs exposed to cocaine underwent differentiation into cells expressing neuronal markers that was associated with an inhibition of SOX2 (SRY-related HMG-box gene 2), a transcription factor that inhibits NPC differentiation [23].
  • In this study, we demonstrate that interaction of the human SRY with histone acetyltransferase p300 induces the acetylation of SRY both in vitro and in vivo at a single conserved lysine residue [24].
  • In calmidazolium-treated cells, the dramatic reduction in nuclear entry of SRY and an SRY-c-NLS mutant was not observed for two SRY-n-NLS mutants [25].
  • An A-to-G transition was detected which leads to an exchange of a tyrosine by a cysteine in the SRY protein [26].
  • This substitution affects a highly conserved tyrosine residue in the HMG box of SRY, in which two de novo mutations have been described previously in XY females with PGD [27].

Physical interactions of SRY

  • The implications of the present results are discussed regarding (a) the apparent dual function of certain basic amino acid residues in the HMG domain of SRY in both DNA binding and in nuclear localization and (b) the possible control of SOX9 in early gonadal differentiation at the level of nuclear translocation [16].
  • Here we report that WT1 binds to and acts synergistically with SRY to activate transcription from a promoter containing SRY-binding sites [2].
  • The proximity of SRY to the pseudoautosomal region (PAR) is highly conserved and thus most effectively stabilizes the pseudoautosomal boundary on the Y (PABY) in simians [28].
  • We hypothesize that SIP-1 could connect SRY to other transcription factors providing SRY for its missing trans-regulation domain [29].
  • Recombinant SRY protein was able to bind to the same core sequence AACAAAG recognized by TCF-1 in a sequence dependent manner [30].

Regulatory relationships of SRY

  • SRY interacts with and negatively regulates androgen receptor transcriptional activity [17].
  • SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors [31].
  • It is suggested here that, rather than acting as a transcriptional activator, the SRY gene acts to inhibit its paralogue SOX3, which in turn inhibits an ancient autosomal sex-determining gene SOX9 [32].
  • The WT1 transcription factor regulates SRY expression during the initial steps of the sex determination process in humans, activating a gene cascade leading to testis differentiation [33].
  • DNA from the blood of 120 men and women and from 38 single lymphocytes was amplified by polymerase chain reaction (PCR) with the SRY and control (ZP3) gene primers [34].

Other interactions of SRY

  • Here we show that SRY and the Sox protein SOX6 colocalize with splicing factors in the nucleus and are dynamically redistributed following the blockage of splicing in living cells [35].
  • SRY protein expression was increased by proteosome inhibitors and by the androgen-liganded AR in transient and stable transfectants [17].
  • This interaction is mediated by the WT1 zinc-finger domain and the SRY HMG box [2].
  • In amniotes, the banded krait minor (Bkm) minisatellite (GATA), the human telometric sequence (TTAGGG)7, and the Y-specific genes, ZFY and SRY, are associated with a particular sex [36].
  • The protein levels of DAX-1, SRY and WT-1 were significantly higher in the bald scalp (p = 0.003, 0.004 and 0.03, respectively) [37].

Analytical, diagnostic and therapeutic context of SRY


  1. True hermaphroditism in a 46,XY individual, caused by a postzygotic somatic point mutation in the male gonadal sex-determining locus (SRY): molecular genetics and histological findings in a sporadic case. Braun, A., Kammerer, S., Cleve, H., Löhrs, U., Schwarz, H.P., Kuhnle, U. Am. J. Hum. Genet. (1993) [Pubmed]
  2. Transcriptional activity of testis-determining factor SRY is modulated by the Wilms' tumor 1 gene product, WT1. Matsuzawa-Watanabe, Y., Inoue, J., Semba, K. Oncogene (2003) [Pubmed]
  3. SRY-negative 46,XX male with normal genitals, complete masculinization and infertility. Rajender, S., Rajani, V., Gupta, N.J., Chakravarty, B., Singh, L., Thangaraj, K. Mol. Hum. Reprod. (2006) [Pubmed]
  4. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. Schooley, R.T., Ruane, P., Myers, R.A., Beall, G., Lampiris, H., Berger, D., Chen, S.S., Miller, M.D., Isaacson, E., Cheng, A.K. AIDS (2002) [Pubmed]
  5. Differential sensitivity of three experimental pain models in detecting the analgesic effects of transdermal fentanyl and buprenorphine. Koltzenburg, M., Pokorny, R., Gasser, U.E., Richarz, U. Pain (2006) [Pubmed]
  6. Sex determination and gonadal development in mammals. Wilhelm, D., Palmer, S., Koopman, P. Physiol. Rev. (2007) [Pubmed]
  7. A 11.7-kb deletion triggers intersexuality and polledness in goats. Pailhoux, E., Vigier, B., Chaffaux, S., Servel, N., Taourit, S., Furet, J.P., Fellous, M., Grosclaude, F., Cribiu, E.P., Cotinot, C., Vaiman, D. Nat. Genet. (2001) [Pubmed]
  8. The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos. Wright, E., Hargrave, M.R., Christiansen, J., Cooper, L., Kun, J., Evans, T., Gangadharan, U., Greenfield, A., Koopman, P. Nat. Genet. (1995) [Pubmed]
  9. Widespread expression of the testis-determining gene SRY in a marsupial. Harry, J.L., Koopman, P., Brennan, F.E., Graves, J.A., Renfree, M.B. Nat. Genet. (1995) [Pubmed]
  10. A de novo phe671eu mutation in the SRY gene in a patient with complete 46,XY gonadal dysgenesis. Zenteno, J.C., Carranza-Lira, S., Jiménez, A.L., Kofman, S. J. Endocrinol. Invest. (2003) [Pubmed]
  11. Identification of an autonomously initiating RNA polymerase III holoenzyme containing a novel factor that is selectively inactivated during protein synthesis inhibition. Wang, Z., Luo, T., Roeder, R.G. Genes Dev. (1997) [Pubmed]
  12. Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir. Sheldon, J., Camino, N., Rodés, B., Bartholomeusz, A., Kuiper, M., Tacke, F., Núñez, M., Mauss, S., Lutz, T., Klausen, G., Locarnini, S., Soriano, V. Antivir. Ther. (Lond.) (2005) [Pubmed]
  13. Antiviral efficacy and genotypic resistance patterns of combination therapy with stavudine/tenofovir in highly active antiretroviral therapy experienced patients. Antinori, A., Trotta, M.P., Nastao, P., Bini, T., Bonora, S., Castagnas, A., Zaccarelli, M., Quirino, T., Landonio, S., Merli, S., Tozzi, V., Di Perri, G., Andreoni, M., Perno, C.F., Carosi, G. Antivir. Ther. (Lond.) (2006) [Pubmed]
  14. Higher risk of hyperglycemia in HIV-infected patients treated with didanosine plus tenofovir. García-Benayas, T., Rendón, A.L., Rodríguez-Novóa, S., Barrios, A., Maida, I., Blanco, F., Barreiro, P., Rivas, P., González-Lahoz, J., Soriano, V. AIDS Res. Hum. Retroviruses (2006) [Pubmed]
  15. Identification and characterization of an Xp22.33;Yp11.2 translocation causing a triplication of several genes of the pseudoautosomal region 1 in an XX male patient with severe systemic lupus erythematosus. Chagnon, P., Schneider, R., Hébert, J., Fortin, P.R., Provost, S., Belisle, C., Gingras, M., Bolduc, V., Perreault, C., Silverman, E., Busque, L. Arthritis Rheum. (2006) [Pubmed]
  16. Two independent nuclear localization signals are present in the DNA-binding high-mobility group domains of SRY and SOX9. Südbeck, P., Scherer, G. J. Biol. Chem. (1997) [Pubmed]
  17. SRY interacts with and negatively regulates androgen receptor transcriptional activity. Yuan, X., Lu, M.L., Li, T., Balk, S.P. J. Biol. Chem. (2001) [Pubmed]
  18. Molecular basis of mammalian sexual determination: activation of Müllerian inhibiting substance gene expression by SRY. Haqq, C.M., King, C.Y., Ukiyama, E., Falsafi, S., Haqq, T.N., Donahoe, P.K., Weiss, M.A. Science (1994) [Pubmed]
  19. Two novel SRY missense mutations reducing DNA binding identified in XY females and their mosaic fathers. Schmitt-Ney, M., Thiele, H., Kaltwasser, P., Bardoni, B., Cisternino, M., Scherer, G. Am. J. Hum. Genet. (1995) [Pubmed]
  20. Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Hawkins, J.R., Taylor, A., Goodfellow, P.N., Migeon, C.J., Smith, K.D., Berkovitz, G.D. Am. J. Hum. Genet. (1992) [Pubmed]
  21. Molecular analysis in true hermaphroditism: demonstration of low-level hidden mosaicism for Y-derived sequences in 46,XX cases. Queipo, G., Zenteno, J.C., Peña, R., Nieto, K., Radillo, A., Dorantes, L.M., Eraña, L., Lieberman, E., Söderlund, D., Jiménez, A.L., Ramón, G., Kofman-Alfaro, S. Hum. Genet. (2002) [Pubmed]
  22. SRY gene expression in the ovotestes of XX true hermaphrodites. Ortenberg, J., Oddoux, C., Craver, R., McElreavey, K., Salas-Cortes, L., Guillen-Navarro, E., Ostrer, H., Sarafoglou, K., Clarke, V., Yee, H. J. Urol. (2002) [Pubmed]
  23. Cocaine alters proliferation, migration, and differentiation of human fetal brain-derived neural precursor cells. Hu, S., Cheeran, M.C., Sheng, W.S., Ni, H.T., Lokensgard, J.R., Peterson, P.K. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  24. Regulation of human SRY subcellular distribution by its acetylation/deacetylation. Thevenet, L., Méjean, C., Moniot, B., Bonneaud, N., Galéotti, N., Aldrian-Herrada, G., Poulat, F., Berta, P., Benkirane, M., Boizet-Bonhoure, B. EMBO J. (2004) [Pubmed]
  25. Defective calmodulin-mediated nuclear transport of the sex-determining region of the Y chromosome (SRY) in XY sex reversal. Sim, H., Rimmer, K., Kelly, S., Ludbrook, L.M., Clayton, A.H., Harley, V.R. Mol. Endocrinol. (2005) [Pubmed]
  26. Description and functional implications of a novel mutation in the sex-determining gene SRY. Poulat, F., Soullier, S., Gozé, C., Heitz, F., Calas, B., Berta, P. Hum. Mutat. (1994) [Pubmed]
  27. Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father. Jordan, B.K., Jain, M., Natarajan, S., Frasier, S.D., Vilain, E. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  28. Simian Y chromosomes: species-specific rearrangements of DAZ, RBM, and TSPY versus contiguity of PAR and SRY. Gläser, B., Grützner, F., Willmann, U., Stanyon, R., Arnold, N., Taylor, K., Rietschel, W., Zeitler, S., Toder, R., Schempp, W. Mamm. Genome (1998) [Pubmed]
  29. The human testis determining factor SRY binds a nuclear factor containing PDZ protein interaction domains. Poulat, F., Barbara, P.S., Desclozeaux, M., Soullier, S., Moniot, B., Bonneaud, N., Boizet, B., Berta, P. J. Biol. Chem. (1997) [Pubmed]
  30. DNA binding activity of recombinant SRY from normal males and XY females. Harley, V.R., Jackson, D.I., Hextall, P.J., Hawkins, J.R., Berkovitz, G.D., Sockanathan, S., Lovell-Badge, R., Goodfellow, P.N. Science (1992) [Pubmed]
  31. SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors. Sekido, R., Bar, I., Narváez, V., Penny, G., Lovell-Badge, R. Dev. Biol. (2004) [Pubmed]
  32. Evolution of the mammalian Y chromosome and sex-determining genes. Graves, J.A. J. Exp. Zool. (1998) [Pubmed]
  33. Mutations in SRY and WT1 genes required for gonadal development are not responsible for XY partial gonadal dysgenesis. Tagliarini, E.B., Assumpção, J.G., Scolfaro, M.R., Mello, M.P., Maciel-Guerra, A.T., Guerra Júnior, G., Hackel, C. Braz. J. Med. Biol. Res. (2005) [Pubmed]
  34. Sex determination of preimplantation embryos by human testis-determining-gene amplification. Cui, K.H., Warnes, G.M., Jeffrey, R., Matthews, C.D. Lancet (1994) [Pubmed]
  35. A direct role of SRY and SOX proteins in pre-mRNA splicing. Ohe, K., Lalli, E., Sassone-Corsi, P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  36. Molecular genetics of sex determination in channel catfish: studies on SRY, ZFY, Bkm, and human telomeric repeats. Tiersch, T.R., Simco, B.A., Davis, K.B., Wachtel, S.S. Biol. Reprod. (1992) [Pubmed]
  37. Expression of sex-determining genes in the scalp of men with androgenetic alopecia. Chen, W., Yang, C.C., Tsai, R.Y., Liao, C.Y., Yen, Y.T., Hung, C.L., Chen, K.F., Tsai, S.J., Zouboulis, C.C. Dermatology (Basel) (2007) [Pubmed]
  38. Paternal transcripts for glucose-6-phosphate dehydrogenase and adenosine deaminase are first detectable in the human preimplantation embryo at the three- to four-cell stage. Taylor, D.M., Ray, P.F., Ao, A., Winston, R.M., Handyside, A.H. Mol. Reprod. Dev. (1997) [Pubmed]
  39. Human sex reversal due to impaired nuclear localization of SRY. A clinical correlation. Li, B., Zhang, W., Chan, G., Jancso-Radek, A., Liu, S., Weiss, M.A. J. Biol. Chem. (2001) [Pubmed]
  40. A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis. Zeng, Y.T., Ren, Z.R., Zhang, M.L., Huang, Y., Zeng, F.Y., Huang, S.Z. J. Med. Genet. (1993) [Pubmed]
  41. A novel missense mutation (S18N) in the 5' non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives. Domenice, S., Yumie Nishi, M., Correia Billerbeck, A.E., Latronico, A.C., Aparecida Medeiros, M., Russell, A.J., Vass, K., Marino Carvalho, F., Costa Frade, E.M., Prado Arnhold, I.J., Bilharinho Mendonca, B. Hum. Genet. (1998) [Pubmed]
  42. Sry associates with the heterochromatin protein 1 complex by interacting with a KRAB domain protein. Oh, H.J., Li, Y., Lau, Y.F. Biol. Reprod. (2005) [Pubmed]
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