SRY and the Genetics of Sex Determination

  • Brian K. Jordan
  • Eric Vilain
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 511)


Many consider the distinction between the two sexes, male and female, to be absolute. Genetic studies of the mechanisms of sexual development have shown the complexity of sex determination and have started to unveil, at the molecular level, how a number of individuals can develop as intersex.


Gonadal Dysgenesis Persistent Mullerian Duct Syndrome Frasier Syndrome Campomelic Dysplasia True Hermaphrodite 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abbas N, McElreavey K, Leconiat M, Vilain E, Jaubert F, Berger R, Nihoul-Fekete C, Rappaport R, Fellous M. Familial case of 46,XX male and 46,XX true hermaphrodite associated with a paternal-derived SRY-bearing X chromosome.Comptes Rendus de L Academie des Sciences. Serie III Sciences de la Vie 316:375–383, 1993.PubMedGoogle Scholar
  2. Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans.Nature Genet22:125–126, 1999.PubMedCrossRefGoogle Scholar
  3. Affara NA, Chalmers 1.1, Ferguson-Smith MA. Analysis of the SRY gene in 22 sex-reversed XY females identifies four new point mutations in the conserved DNA binding domain.Hum Mol Genet2:785–789, 1993.PubMedCrossRefGoogle Scholar
  4. Am P, Chen Ii, Tuck-Muller CM, Mankinen C, Wachtel G, Li S, Shen CC, Wachtel SS. SRVX, a sex reversing locus in Xp21.2->p22.1 1. HumGenet93:389–393, 1994.Google Scholar
  5. Barbaux S, Niaudet P, Gublcr MC, Grunfeld JP, Jaubert F, Kuttenn F, Feketc CN, Souleyrcau-Therville N, Thibaud E, Fellous M, McElreavey K. Donor splice-site mutations in WTI are responsible for Frasier syndrome.Nature Genet17:467–470, 1997.PubMedCrossRefGoogle Scholar
  6. Bardeesy N, Zabel B, Schmitt K, Pelletier J. WTI mutations associated with incomplete Denys-Drash syndrome define a domain predicted to behave in a dominant-negative fashion.Genomics21:663–664, 1994.PubMedCrossRefGoogle Scholar
  7. Bardoni B, Zanaria F, Guioli S, Floridia G, Worley KC, Tonini G, Ferrante E, Chiumello G, McCabe ERB, Fraccaro M, Zuffardi O, Camerino G. A dosage sensitive locus at chromosome Xp2 I is involved in male to female sex reversal.Nature Genet7:497–501, 1994.PubMedCrossRefGoogle Scholar
  8. Behringer RR, Finegold MJ, Cate RL. Müllerian-inhibiting substance function during mammalian sexual development.Cell79:415–425, 1994.PubMedCrossRefGoogle Scholar
  9. Bell DM, Leung KK, Wheatley SC, Ng LI, Zhou S, Ling KW, Sham Mit, Koopman P, Tam PP, Cheah KS. SOX9 directly regulates the type-II collagen gene.Nature Genet16:174–178,1997.PubMedCrossRefGoogle Scholar
  10. Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths B, Goodfellow PN, Fellous M. Genetic evidence equating SRY and the testis-determining factor.Nature348:448–450, 1990.PubMedCrossRefGoogle Scholar
  11. Bowles J, Cooper L, Berkman J, Koopman P. Sry requires a CAG repeat domain for male sex determination inMus musculus. Nature Genet22:405–408, 1999.CrossRefGoogle Scholar
  12. Brown S, Yu C, Lanzano P, Ileller D, Thomas L, Warburton D, Kitajewski.J, Stadtmauer L. A de novo mutation (G1n2Stop) at the 5’ end of the SRY gene leads to sex reversal with partial ovarian function.Am J Hum Genet62:189–192, 1998.PubMedCrossRefGoogle Scholar
  13. Burris TP, Guo W, Le T, McCabe ERB. Identification of a putative steroidogenic factor-I response element in the DAX-1 promoter.Biochem Biophys Res Commun214:576–581, 1995.PubMedCrossRefGoogle Scholar
  14. Clépet C, Schafer AJ, Sinclair Aft, Palmer MS, Lovell-Badge R, Goodfellow PN. The human SRY transcript.Hum Mol Genet2:2007–2012, 1993.Google Scholar
  15. de Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P. Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Miillerian hormone gene.Mol Cell Bio! 18:6653–6665, 1998.Google Scholar
  16. Desclozeaux M, Poulat F, de Santa Barbara P, Capony JP, Turowski P, Jay P, Méjean C, Moniot B, Boizet B, Berta P. Phosphorylation of an N-terminal motif enhances DNA-binding activity of the human SRY protein.J Biol Chem273:7988–7995, 1998.PubMedCrossRefGoogle Scholar
  17. Domenice S, Yumie Nishi M, Correia Billerbeck AE, Latronico AC, Aparecida Medeiros M, Russell AJ, Vass K, Marino Carvalho F, Costa Frade EM, Prado Amhold IJ, Bilharinho Mendonca B. 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.Hum Genet102:213–215, 1998.PubMedCrossRefGoogle Scholar
  18. Dubin RA, Ostrer H. SRY is a transcriptional activator.Mol Endocrinol8:1182–1192, 1994.PubMedCrossRefGoogle Scholar
  19. Ferguson-Smith MA. X-Y chromosomal interchange in the aetiology of true hermaphroditism and of XX Klinefelter’s syndrome.Lancetii:475–476, 1966.Google Scholar
  20. Ferrari S, Harley VR, Pontiggia A, Goodfellow PN, Lovell-Badge R, Bianchi ME. SRY, like HMGI, recognizes sharp angles in DNA.Embu J11:4497–4506,1992.Google Scholar
  21. Ford CE, Jones KW, Polani PE, de Almeida JC, Brigg JH. A sex chromosome anomaly in a case of gonadal dysgenesis (Tuner syndrome).Lancet1:711–713, 1959.PubMedCrossRefGoogle Scholar
  22. Foster JW, Dominguez-Steglich MA, Guili S, Kowk G, Weller PA, Stefanovic M, Weissenbach J, Mansour S, Young ID, Goodfellow PN. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.Nature372:525–529, 1994.PubMedCrossRefGoogle Scholar
  23. Giese K, Cox J, Grosschedl R. The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures.Cell69:185–195, 1992.PubMedCrossRefGoogle Scholar
  24. Giese K, Pagel J, Grosschedl R. Distinct DNA-binding properties of the high mobility group domain of murine and human SRY sex-determining factors.Proc Natl Acad Sci USA91:3368–3372, 1994.PubMedCrossRefGoogle Scholar
  25. Grumbach MM, Conte FA. Disorders of sex differentiation, in:Williams Textbook of EndocrinologyEdition, Wilson, Foster, Kronenberg, Larsen, eds., Saunders, Philadelphia, 1998.Google Scholar
  26. Guo W, Burris TP, McCabe ERB. Expression of DAX-1, the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism, in the hypothalamic-pituitary-adrenal/gonadal axis.Biochem Mol Med56:8–13, 1995.PubMedCrossRefGoogle Scholar
  27. Guo W, Burris TP-hang YH, Huang BL, Mason J, Copeland KC, Kupfer SR, Pagon RA, McCabe ERB. Genomic sequence of the DAXI gene: an orphan nuclear receptor responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. J Clin Endocrinol Metab81:2481–2486, 1996.PubMedCrossRefGoogle Scholar
  28. Harley VR, Jackson DI, Hextall PJ, Hawkins JR, Berkovitz GD, Sockanathan S, Lovell-Badge R, Goodfellow PN. DNA binding activity of recombinant SRY from normal males and XY females.Science255:453–455, 1992.PubMedCrossRefGoogle Scholar
  29. Harley V, Lovell-Badge R, Goodfellow PN. Definition of a consensus DNA binding site for SRY.Nucl Acids Res22:1500–1501, 1994.PubMedCrossRefGoogle Scholar
  30. Harley VR, Lovell-Badge R, Goodfellow PN, Hextall PJ. The HMG box of SRY is a calmodulin binding domain.Febs Letters391:24–28, 1996.PubMedCrossRefGoogle Scholar
  31. Hawkins.JR, Taylor A, Berta P, Levilliers J, Van der Auwera B, Goodfellow PN. Mutational analysis of SRY: nonsense and missense mutations in XV sex reversal.Hum Genet88:471–474, 1992a.PubMedCrossRefGoogle Scholar
  32. Hawkins JR, Taylor A, Goodfellow PN, Migeon CJ, Smith KD, Berkovitz GD. Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis.Am J Hum Genet51:979–984, 1992b.PubMedGoogle Scholar
  33. Huang B, Wang S, Ning Y, Lamb AN, Bartley J. Autosomal XX sex reversal caused by duplication of SOX9. Proceedings of the 49thmeeting of the American Society of Human Genetics, Oct 1999, San Francisco, published inAm JHum Genet65:A6, 1999.Google Scholar
  34. Ikeda Y, Shen W-H, Ingraham HA, Parker KL. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases.Mol Endocrino!8:654–662, 1994.CrossRefGoogle Scholar
  35. Ito M, Yu R, Jameson JL. DAX-I inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita.Mol Cell Bio117:1476–83, 1997.Google Scholar
  36. Jacobs PA, Strong JA. A case of human intersexuality having a possible XXII sex-determining mechanism.Nature183:302–303, 1959.PubMedCrossRefGoogle Scholar
  37. Jäger RJ, Anvret M, Hall K, Scherer G. A human XY female with frame shift mutation in the candidate sex determining gene, SRY.Nature348:452–454. 1990.PubMedCrossRefGoogle Scholar
  38. Jäger R, Harley VR, Pfeiffer RA, Goodfellow PN, Scherer G. A familial mutation in the testis-determining gene SRY shared by both sexes.Hum Genet90:350–355. 1992.PubMedCrossRefGoogle Scholar
  39. Jantzen HM, Admon A, Bell SP, Tjian R. Nucleolar transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins.Nature344:830–836, 1990.PubMedCrossRefGoogle Scholar
  40. Jost A. Recherches sur la différenciation sexuelle de l’embryon de lapin. III. 1161e des gonades foetales dans la différenciation sexuelle somatique.Arch Anal Microsc Morphol Exp36:271–315, 1947.Google Scholar
  41. Koopman P, Munserberg A, Cape B, Vivian N, Lovell-Badge R. Expression of a candidate sex-determining gene during mouse testis differentiation.Nature348:450–452. 1990.PubMedCrossRefGoogle Scholar
  42. Koopman P, Gubbay J, Vivian N, Goodfellow PN., Lovell-Badge R. Male development of chromosomally female mice transgenic for SRY.Nature351:117–121, 1991.PubMedCrossRefGoogle Scholar
  43. Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R. WT-I is required for early kidney development.Cell74:679–691, 1993.PubMedCrossRefGoogle Scholar
  44. Lahr G, Maxson SC, Mayer A, Just W, Pilgrim C, Reisert I. Transcription of the Y chromosomal geneSRYin adult mouse brain. Molecular Brain Research33:179–82, 1995.PubMedCrossRefGoogle Scholar
  45. Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation.Cell77:481–490, 1994.PubMedCrossRefGoogle Scholar
  46. McElreavey K, Vilain E, Abbas N, Costa J-M, Souleyreau N, Kucheria K, Boucekkine C, Thibault E, Flamant F, Fellous M. XY sex-reversal associated with a deletion 5’ to the SRY HMG-box in the testis-determiningregion.Proc Nall Acad Sci USA89:11016–11020, 1992a.CrossRefGoogle Scholar
  47. McElreavey K, Vilain E, Boucekkine C, Vidaud M, Jaubert F, Richaud F, Fellous M. XY sex reversal associated with a nonsense mutation in SRY.Genomics13:838–840, 1992b.PubMedCrossRefGoogle Scholar
  48. McElreavey K, Vilain E, Abbas N, Herskowitz I, Fellous M. A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development.Proc Natl Amid Sci USA90:3368–3372. 1993.CrossRefGoogle Scholar
  49. McElreavey K, Barbaux S, Ion A, Fellous M. The genetic basis of murine and human sex determination: a review.Heredity75:599–611, 1995.PubMedCrossRefGoogle Scholar
  50. Müller J, Schwartz M., Skakkebaek NE. Analysis of the sex determining region of the Y chromosome (SRY) in sex reversed patients: point mutation in SRY causing sex reversion in a 46, XY female.J Clin Endocrinol Metabol75:331–333, 1992.CrossRefGoogle Scholar
  51. Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA. Wilms’ tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.Cell93:445–454, 1998.PubMedCrossRefGoogle Scholar
  52. Ohno S.Major sex-determining genesSpringer Verlag, New York, 1979.CrossRefGoogle Scholar
  53. Oreal E, Pieau C, Mattei MG, Josso N, Picard JY, Carré-Eusèbe D, Magre S. Early expression of AMH in chicken embryonic gonads precedes testicular SOX9 expression.Dev Dyn212:522–532, 1998.PubMedCrossRefGoogle Scholar
  54. Palmer MS, Sinclair AH, Berta P, Ellis NA, Goodfellow PN, Abbas NE, Fellous M. Genetic evidence that ZFY is not the testis-determining factor.Nature342:937–939, 1989.PubMedCrossRefGoogle Scholar
  55. Pelletier J, Bruening W, Li FP, Glaser T, Haber, DA. & Housman, D. WTI mutations contribute to abnormal genital system development and hereditary Wilm’s tumor.Nature353:431–434, 1991a.PubMedCrossRefGoogle Scholar
  56. Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, Fine RN, Silverman BL, Haber DA, Housman D. Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.Cell67:437–447, 1991b.PubMedCrossRefGoogle Scholar
  57. Poulat F, Soullier S, Goze C, Heitz F, Calas B, Berta P. Description and functional implications of a novel mutation in the sex-determining gene SRY.Hum Mutat3:200–204, 1994.PubMedCrossRefGoogle Scholar
  58. Poulat F, De Santa Barbara P, Desclozeaux M, Soullier S, Moniot B, Bonneaud N, Boizet B, Berta P. The human testis determining factor SRY binds a nuclear factor containing PDZ protein interaction domains.J Biol Chem272:7167–7172, 1997.PubMedCrossRefGoogle Scholar
  59. Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS. Androgen receptor defects: historical, clinical, and molecular.Endocrine Rev16:271–321, 1995.Google Scholar
  60. Sinclair AH, Berta P, Palmer MS, Hawkin JR, Griffiths BL, Smith Mi, Foster J. M, Frischauf AM, Lovell-Badge R, Goodfellow PN. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA binding motif.Nature346:240–244, 1990.PubMedCrossRefGoogle Scholar
  61. Swain A, Zanaria E, Hacker A, Lovell-Badge R, Camerino G. Mouse DAX1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function.Nature Genet12:404–409, 1996.PubMedCrossRefGoogle Scholar
  62. Swain A, Narvaez V, Burgoyne P, Camerino G, Lovell-Badge R. DAX1 antagonizes SRY action in mammalian sex determination.Nature391:761–767, 1998.PubMedCrossRefGoogle Scholar
  63. Tajima J, Nakae J, Shinohara N, Fujieda K. A novel mutation localized in the 3’ non-HMG box region of the SRY gene in 46, XY gonadal dysgenesis.Hum Mol Genet3:1187–1189, 1994.PubMedCrossRefGoogle Scholar
  64. Tommerup N, Schempp W, Meinecke P, Pedersen S, Bolund L, Brandt C, Goodpasture C, Guldberg P, Held KR, Reinwein H, et al. Assignment of an autosomal sex reversal locus (SRAI) and campomelic dysplasia (CMPD 1) to 17g24.3–825.1.Nature Genet4:3–825, 1993.PubMedCrossRefGoogle Scholar
  65. Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP. Female development in mammals is regulated by Wnt-4 signalling.Nature397:405–409, 1999.PubMedCrossRefGoogle Scholar
  66. van de Wetering M, Clevers H. Sequence-specific interaction of the HMG box proteins TCF-I and SRY occurs within the minor groove of a Watson-Crick double helix.Embo J11: 3039–3044, 1992.PubMedGoogle Scholar
  67. Vilain E, McElreavey K, Jaubert F, Raymond J-P, Richaud F, Fellous M. Familial case with sequence variant in the testis-determining region associated with two sex phenotypes.Am J Hum Genet50:1008–1011, 1992a.PubMedGoogle Scholar
  68. Vilain E, McElreavey K, Herskowitz I, Fellous M. La détermination du sexe: faits et nouveaux concepts.Médecine/Sciences8:I-VII. 1992b.Google Scholar
  69. Vilain E, Fellous M, McElreavey K. Characterization and sequence of the 5’-flanking region of the human testis determining factor SRY.Methods Mol Cell Biol3:128–134, 1992c.Google Scholar
  70. Vilain E, Lefiblec B, Morichon-Delvallez N, Brauner R, Dommergues M, Dumez Y, Jaubert F, Boucekkine C, McElreavey K, Vekemans M, Fellous M. SRY-negative XX fetus with complete male phenotype.Lancet343:240–241,1994.PubMedCrossRefGoogle Scholar
  71. Vilain E, Guo W, Zhang YH, McCabe ER. DAXI gene expression upregulated by steroidogenic factor I in an adrenocortical carcinoma cell line.Biochem Mol Med61:1–8, 1997.PubMedCrossRefGoogle Scholar
  72. Wagner T, Wirth J, Meyer J, Zabel, B, Held M, Zimmer J, Pasantes J, Bricarelli FD, Keutel J, Hastert E, Wolf U, Tommerup N, Schempp W, Sherer G. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.Cell79:1111–1120, 1994.PubMedCrossRefGoogle Scholar
  73. Waterman ML, Fischer WH, Jones KA. A thymus-specific member of the HMG protein family regulates the human T cell receptor C a enhancer.Genes Dey5:656–669, 1991.CrossRefGoogle Scholar
  74. White PC, New MI, Dupont B. Congenital adrenal hyperplasia.New Eng J Med316:1519–1524, 1987.PubMedCrossRefGoogle Scholar
  75. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ERB, Meitinger T, Monaco AP, Sassone-Corsi P, Camerino G. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita.Nature372:635–641, 1994.PubMedCrossRefGoogle Scholar
  76. Zazopoulos E, Lalli E, Stocco DM, Sassone-Corsi P. DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis.Nature390:311–315, 1997.PubMedCrossRefGoogle Scholar
  77. Zeng YT, Ren ZR, Zhang ML, Huang Y, Zeng FY, Huang SZ. A new de novo mutation (Al 13T) in HMG box of the SRY gene leads to XY gonadal dysgenesis.JMed Genet30:655–657, 1993.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Brian K. Jordan
    • 1
  • Eric Vilain
    • 1
  1. 1.Department of Human GeneticsUCLA School of MedicineLos AngelesUSA

Personalised recommendations