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Pediatric Gender Assignment pp 1–14Cite as

SRY and the Genetics of Sex Determination

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 511))

Abstract

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.

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References

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Behringer RR, Finegold MJ, Cate RL. Müllerian-inhibiting substance function during mammalian sexual development.Cell79:415–425, 1994.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Dubin RA, Ostrer H. SRY is a transcriptional activator.Mol Endocrinol8:1182–1192, 1994.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Grumbach MM, Conte FA. Disorders of sex differentiation, in:Williams Textbook of EndocrinologyEdition, Wilson, Foster, Kronenberg, Larsen, eds., Saunders, Philadelphia, 1998.

    Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Harley V, Lovell-Badge R, Goodfellow PN. Definition of a consensus DNA binding site for SRY.Nucl Acids Res22:1500–1501, 1994.

    Article  PubMed  CAS  Google Scholar 

  • Harley VR, Lovell-Badge R, Goodfellow PN, Hextall PJ. The HMG box of SRY is a calmodulin binding domain.Febs Letters391:24–28, 1996.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • Jacobs PA, Strong JA. A case of human intersexuality having a possible XXII sex-determining mechanism.Nature183:302–303, 1959.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Koopman P, Gubbay J, Vivian N, Goodfellow PN., Lovell-Badge R. Male development of chromosomally female mice transgenic for SRY.Nature351:117–121, 1991.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • McElreavey K, Barbaux S, Ion A, Fellous M. The genetic basis of murine and human sex determination: a review.Heredity75:599–611, 1995.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Ohno S.Major sex-determining genesSpringer Verlag, New York, 1979.

    Book  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Swain A, Narvaez V, Burgoyne P, Camerino G, Lovell-Badge R. DAX1 antagonizes SRY action in mammalian sex determination.Nature391:761–767, 1998.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP. Female development in mammals is regulated by Wnt-4 signalling.Nature397:405–409, 1999.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Vilain E, McElreavey K, Herskowitz I, Fellous M. La détermination du sexe: faits et nouveaux concepts.Médecine/Sciences8:I-VII. 1992b.

    Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • White PC, New MI, Dupont B. Congenital adrenal hyperplasia.New Eng J Med316:1519–1524, 1987.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Zazopoulos E, Lalli E, Stocco DM, Sassone-Corsi P. DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis.Nature390:311–315, 1997.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Human Genetics, UCLA School of Medicine, Los Angeles, California, USA

    Brian K. Jordan & Eric Vilain

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  1. Brian K. Jordan
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  2. Eric Vilain
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  1. Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Stephen A. Zderic , Douglas A. Canning , Michael C. Carr  & Howard McC. Snyder III. , ,  & 

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Jordan, B.K., Vilain, E. (2002). SRY and the Genetics of Sex Determination. In: Zderic, S.A., Canning, D.A., Carr, M.C., Snyder, H.M. (eds) Pediatric Gender Assignment. Advances in Experimental Medicine and Biology, vol 511. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0621-8_1

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