Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Aug 6;93(16):8590–8594. doi: 10.1073/pnas.93.16.8590

Loss of sequences 3' to the testis-determining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination.

K McElreavey 1, E Vilain 1, S Barbaux 1, J S Fuqua 1, P Y Fechner 1, N Souleyreau 1, M Doco-Fenzy 1, R Gabriel 1, C Quereux 1, M Fellous 1, G D Berkovitz 1
PMCID: PMC38717  PMID: 8710915

Abstract

The condition termed 46,XY complete gonadal dysgenesis is characterized by a completely female phenotype and streak gonads. In contrast, subjects with 46,XY partial gonadal dysgenesis and those with embryonic testicular regression sequence usually present ambiguous genitalia and a mix of Müllerian and Wolffian structures. In 46,XY partial gonadal dysgenesis gonadal histology shows evidence of incomplete testis determination. In 46,XY embryonic testicular regression sequence there is lack of gonadal tissue on both sides. Various lines of evidence suggest that embryonic testicular regression sequence is a variant form of 46,XY gonadal dysgenesis. The sex-determining region Y chromosome gene (SRY) encodes sequences for the testis-determining factor. To date germ-line mutations in SRY have been reported in approximately 20% of subjects with 46,XY complete gonadal dysgenesis. However, no germ-line mutations of SRY have been reported in subjects with the partial forms. We studied 20 subjects who presented either 46,XY partial gonadal dysgenesis or 46,XY embryonic testicular regression sequence. We examined the SRY gene and the minimum region of Y-specific DNA known to confer a male phenotype. The SRY-open reading frame (ORF) was normal in all subjects. However a de novo interstitial deletion 3' to the SRY-ORF was found in one subject. Although it is possible that the deletion was unrelated to the subject's phenotype, we propose that the deletion was responsible for the abnormal gonadal development by diminishing expression of SRY. We suggest that the deletion resulted either in the loss of sequences necessary for normal SRY expression or in a position effect that altered SRY expression. This case provides further evidence that deletions of the Y chromosome outside the SRY-ORF can result in either complete or incomplete sex reversal.

Full text

PDF
8590

Images in this article

8592Fig. 1
on p.8592
8592Fig. 2
on p.8592
8593Fig. 3
on p.8593

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Affara N. A., Chalmers I. J., Ferguson-Smith M. A. Analysis of the SRY gene in 22 sex-reversed XY females identifies four new point mutations in the conserved DNA binding domain. Hum Mol Genet. 1993 Jun;2(6):785–789. doi: 10.1093/hmg/2.6.785. [DOI] [PubMed] [Google Scholar]
  2. Affara N. A., Ferguson-Smith M. A., Tolmie J., Kwok K., Mitchell M., Jamieson D., Cooke A., Florentin L. Variable transfer of Y-specific sequences in XX males. Nucleic Acids Res. 1986 Jul 11;14(13):5375–5387. doi: 10.1093/nar/14.13.5375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bardoni B., Zanaria E., Guioli S., Floridia G., Worley K. C., Tonini G., Ferrante E., Chiumello G., McCabe E. R., Fraccaro M. A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nat Genet. 1994 Aug;7(4):497–501. doi: 10.1038/ng0894-497. [DOI] [PubMed] [Google Scholar]
  4. Behlke M. A., Bogan J. S., Beer-Romero P., Page D. C. Evidence that the SRY protein is encoded by a single exon on the human Y chromosome. Genomics. 1993 Sep;17(3):736–739. doi: 10.1006/geno.1993.1395. [DOI] [PubMed] [Google Scholar]
  5. Berkovitz G. D. Abnormalities of gonadal determination and differentiation. Semin Perinatol. 1992 Oct;16(5):289–298. [PubMed] [Google Scholar]
  6. Berkovitz G. D., Fechner P. Y., Zacur H. W., Rock J. A., Snyder H. M., 3rd, Migeon C. J., Perlman E. J. Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation. Medicine (Baltimore) 1991 Nov;70(6):375–383. doi: 10.1097/00005792-199111000-00003. [DOI] [PubMed] [Google Scholar]
  7. Berta P., Hawkins J. R., Sinclair A. H., Taylor A., Griffiths B. L., Goodfellow P. N., Fellous M. Genetic evidence equating SRY and the testis-determining factor. Nature. 1990 Nov 29;348(6300):448–450. doi: 10.1038/348448A0. [DOI] [PubMed] [Google Scholar]
  8. Braun A., Kammerer S., Cleve H., Löhrs U., Schwarz H. P., Kuhnle U. 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. Am J Hum Genet. 1993 Mar;52(3):578–585. [PMC free article] [PubMed] [Google Scholar]
  9. Burk R. D., Szabo P., O'Brien S., Nash W. G., Yu L., Smith K. D. Organization and chromosomal specificity of autosomal homologs of human Y chromosome repeated DNA. Chromosoma. 1985;92(3):225–233. doi: 10.1007/BF00348698. [DOI] [PubMed] [Google Scholar]
  10. Capel B., Rasberry C., Dyson J., Bishop C. E., Simpson E., Vivian N., Lovell-Badge R., Rastan S., Cattanach B. M. Deletion of Y chromosome sequences located outside the testis determining region can cause XY female sex reversal. Nat Genet. 1993 Nov;5(3):301–307. doi: 10.1038/ng1193-301. [DOI] [PubMed] [Google Scholar]
  11. Cooke H. J., Fantes J., Green D. Structure and evolution of human Y chromosome DNA. Differentiation. 1983;23 (Suppl):S48–S55. doi: 10.1007/978-3-642-69150-8_9. [DOI] [PubMed] [Google Scholar]
  12. Eicher E. M., Washburn L. L. Inherited sex reversal in mice: identification of a new primary sex-determining gene. J Exp Zool. 1983 Nov;228(2):297–304. doi: 10.1002/jez.1402280213. [DOI] [PubMed] [Google Scholar]
  13. Ellis N., Taylor A., Bengtsson B. O., Kidd J., Rogers J., Goodfellow P. Population structure of the human pseudoautosomal boundary. Nature. 1990 Apr 12;344(6267):663–665. doi: 10.1038/344663a0. [DOI] [PubMed] [Google Scholar]
  14. Foster J. W., Dominguez-Steglich M. A., Guioli S., Kwok C., Weller P. A., Stevanović M., Weissenbach J., Mansour S., Young I. D., Goodfellow P. N. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. 1994 Dec 8;372(6506):525–530. doi: 10.1038/372525a0. [DOI] [PubMed] [Google Scholar]
  15. Fraizer G. C., Wu Y. J., Hewitt S. M., Maity T., Ton C. C., Huff V., Saunders G. F. Transcriptional regulation of the human Wilms' tumor gene (WT1). Cell type-specific enhancer and promiscuous promoter. J Biol Chem. 1994 Mar 25;269(12):8892–8900. [PubMed] [Google Scholar]
  16. Hawkins J. R., Taylor A., Berta P., Levilliers J., Van der Auwera B., Goodfellow P. N. Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet. 1992 Feb;88(4):471–474. doi: 10.1007/BF00215684. [DOI] [PubMed] [Google Scholar]
  17. Hawkins J. R., Taylor A., Goodfellow P. N., Migeon C. J., Smith K. D., Berkovitz G. D. Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J Hum Genet. 1992 Nov;51(5):979–984. [PMC free article] [PubMed] [Google Scholar]
  18. Hiort O., Gramss B., Klauber G. T. True hermaphroditism with 46,XY karyotype and a point mutation in the SRY gene. J Pediatr. 1995 Jun;126(6):1022–1022. doi: 10.1016/s0022-3476(95)70247-4. [DOI] [PubMed] [Google Scholar]
  19. Jeffreys A. J., Wilson V., Thein S. L. Individual-specific 'fingerprints' of human DNA. Nature. 1985 Jul 4;316(6023):76–79. doi: 10.1038/316076a0. [DOI] [PubMed] [Google Scholar]
  20. Jäger R. J., Anvret M., Hall K., Scherer G. A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature. 1990 Nov 29;348(6300):452–454. doi: 10.1038/348452a0. [DOI] [PubMed] [Google Scholar]
  21. Kelly M., Burke J., Smith M., Klar A., Beach D. Four mating-type genes control sexual differentiation in the fission yeast. EMBO J. 1988 May;7(5):1537–1547. doi: 10.1002/j.1460-2075.1988.tb02973.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Marcantonio S. M., Fechner P. Y., Migeon C. J., Perlman E. J., Berkovitz G. D. Embryonic testicular regression sequence: a part of the clinical spectrum of 46,XY gonadal dysgenesis. Am J Med Genet. 1994 Jan 1;49(1):1–5. doi: 10.1002/ajmg.1320490102. [DOI] [PubMed] [Google Scholar]
  23. McElreavy K., Vilain E., Abbas N., Costa J. M., Souleyreau N., Kucheria K., Boucekkine C., Thibaud E., Brauner R., Flamant F. XY sex reversal associated with a deletion 5' to the SRY "HMG box" in the testis-determining region. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):11016–11020. doi: 10.1073/pnas.89.22.11016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Page D. C., Mosher R., Simpson E. M., Fisher E. M., Mardon G., Pollack J., McGillivray B., de la Chapelle A., Brown L. G. The sex-determining region of the human Y chromosome encodes a finger protein. Cell. 1987 Dec 24;51(6):1091–1104. doi: 10.1016/0092-8674(87)90595-2. [DOI] [PubMed] [Google Scholar]
  25. Palmer M. S., Sinclair A. H., Berta P., Ellis N. A., Goodfellow P. N., Abbas N. E., Fellous M. Genetic evidence that ZFY is not the testis-determining factor. Nature. 1989 Dec 21;342(6252):937–939. doi: 10.1038/342937a0. [DOI] [PubMed] [Google Scholar]
  26. Palmer S. J., Burgoyne P. S. The Mus musculus domesticus Tdy allele acts later than the Mus musculus musculus Tdy allele: a basis for XY sex-reversal in C57BL/6-YPOS mice. Development. 1991 Oct;113(2):709–714. doi: 10.1242/dev.113.2.709. [DOI] [PubMed] [Google Scholar]
  27. Pelletier J., Bruening W., Kashtan C. E., Mauer S. M., Manivel J. C., Striegel J. E., Houghton D. C., Junien C., Habib R., Fouser L. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell. 1991 Oct 18;67(2):437–447. doi: 10.1016/0092-8674(91)90194-4. [DOI] [PubMed] [Google Scholar]
  28. Sinclair A. H., Berta P., Palmer M. S., Hawkins J. R., Griffiths B. L., Smith M. J., Foster J. W., Frischauf A. M., Lovell-Badge R., Goodfellow P. N. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990 Jul 19;346(6281):240–244. doi: 10.1038/346240a0. [DOI] [PubMed] [Google Scholar]
  29. Smith K. D., Young K. E., Talbot C. C., Jr, Schmeckpeper B. J. Repeated DNA of the human Y chromosome. Development. 1987;101 (Suppl):77–92. doi: 10.1242/dev.101.Supplement.77. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES