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. 1999 Jun;36(6):452–456.

Incomplete masculinisation of XX subjects carrying the SRY gene on an inactive X chromosome

K Kusz 1, M Kotecki 1, A Wojda 1, M Szarras-Czapnik 1, A Latos-Bielenska 1, A Warenik-Szymankie 1, A Ruszczynska-Wolsk 1, J Jaruzelska 1
PMCID: PMC1734388  PMID: 10874632

Abstract

46,XX subjects carrying the testis determining SRY gene usually have a completely male phenotype. In this study, five very rare cases of SRY carrying subjects (two XX males and three XX true hermaphrodites) with various degrees of incomplete masculinisation were analysed in order to elucidate the cause of sexual ambiguity despite the presence of the SRY gene. PCR amplification of 20 Y chromosome specific sequences showed the Yp fragment to be much longer in XX males than in true hermaphrodites. FISH analysis combined with RBG banding of metaphase chromosomes of four patients showed that in all three true hermaphrodites and in one XX male the Yp fragment was translocated onto a late replicating inactive X chromosome in over 90% of their blood lymphocytes. However, in a control classical XX male with no ambiguous features, the Yp fragment (significantly shorter than in the XX male with sexual ambiguity and only slightly longer than in XX hermaphrodites) was translocated onto the active X chromosome in over 90% of cells.
These studies strongly indicate that inactivation on the X chromosome spreading into a translocated Yp fragment could be the major mechanism causing a sexually ambiguous phenotype in XX (SRY+) subjects.


Keywords: sex determination; X inactivation; SRY gene

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Selected References

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  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. C R Acad Sci III. 1993;316(4):375–383. [PubMed] [Google Scholar]
  2. Berkovitz G. D., Fechner P. Y., Marcantonio S. M., Bland G., Stetten G., Goodfellow P. N., Smith K. D., Migeon C. J. The role of the sex-determining region of the Y chromosome (SRY) in the etiology of 46,XX true hermaphroditism. Hum Genet. 1992 Feb;88(4):411–416. doi: 10.1007/BF00215675. [DOI] [PubMed] [Google Scholar]
  3. Bogan J. S., Page D. C. Ovary? Testis?--A mammalian dilemma. Cell. 1994 Feb 25;76(4):603–607. doi: 10.1016/0092-8674(94)90501-0. [DOI] [PubMed] [Google Scholar]
  4. Boucekkine C., Toublanc J. E., Abbas N., Chaabouni S., Ouahid S., Semrouni M., Jaubert F., Toublanc M., McElreavey K., Vilain E. Clinical and anatomical spectrum in XX sex reversed patients. Relationship to the presence of Y specific DNA-sequences. Clin Endocrinol (Oxf) 1994 Jun;40(6):733–742. doi: 10.1111/j.1365-2265.1994.tb02506.x. [DOI] [PubMed] [Google Scholar]
  5. Boucekkine C., Toublanc J. E., Abbas N., Semrouni M., Vilain E., McElreavey K., Mugneret F., Fellous M. The sole presence of the testis-determining region of the Y chromosome (SRY) in 46,XX patients is associated with phenotypic variability. Horm Res. 1992;37(6):236–240. doi: 10.1159/000182319. [DOI] [PubMed] [Google Scholar]
  6. Fechner P. Y., Marcantonio S. M., Jaswaney V., Stetten G., Goodfellow P. N., Migeon C. J., Smith K. D., Berkovitz G. D., Amrhein J. A., Bard P. A. The role of the sex-determining region Y gene in the etiology of 46,XX maleness. J Clin Endocrinol Metab. 1993 Mar;76(3):690–695. doi: 10.1210/jcem.76.3.8383144. [DOI] [PubMed] [Google Scholar]
  7. Fechner P. Y., Rosenberg C., Stetten G., Cargile C. B., Pearson P. L., Smith K. D., Migeon C. J., Berkovitz G. D. Nonrandom inactivation of the Y-bearing X chromosome in a 46,XX individual: evidence for the etiology of 46,XX true hermaphroditism. Cytogenet Cell Genet. 1994;66(1):22–26. doi: 10.1159/000133656. [DOI] [PubMed] [Google Scholar]
  8. Ferguson-Smith M. A., Cooke A., Affara N. A., Boyd E., Tolmie J. L. Genotype-phenotype correlations in XX males and their bearing on current theories of sex determination. Hum Genet. 1990 Jan;84(2):198–202. doi: 10.1007/BF00208942. [DOI] [PubMed] [Google Scholar]
  9. Ferguson-Smith M. A. X-Y chromosomal interchange in the aetiology of true hermaphroditism and of XX Klinefelter's syndrome. Lancet. 1966 Aug 27;2(7461):475–476. doi: 10.1016/s0140-6736(66)92778-4. [DOI] [PubMed] [Google Scholar]
  10. Foote S., Vollrath D., Hilton A., Page D. C. The human Y chromosome: overlapping DNA clones spanning the euchromatic region. Science. 1992 Oct 2;258(5079):60–66. doi: 10.1126/science.1359640. [DOI] [PubMed] [Google Scholar]
  11. Goodfellow P. N., Lovell-Badge R. SRY and sex determination in mammals. Annu Rev Genet. 1993;27:71–92. doi: 10.1146/annurev.ge.27.120193.000443. [DOI] [PubMed] [Google Scholar]
  12. Hadjiathanasiou C. G., Brauner R., Lortat-Jacob S., Nivot S., Jaubert F., Fellous M., Nihoul-Fékété C., Rappaport R. True hermaphroditism: genetic variants and clinical management. J Pediatr. 1994 Nov;125(5 Pt 1):738–744. doi: 10.1016/s0022-3476(94)70067-2. [DOI] [PubMed] [Google Scholar]
  13. Hawkins J. R. Sex determination. Hum Mol Genet. 1994;3(Spec No):1463–1467. doi: 10.1093/hmg/3.suppl_1.1463. [DOI] [PubMed] [Google Scholar]
  14. Jäger R. J., Ebensperger C., Fraccaro M., Scherer G. A ZFY-negative 46,XX true hermaphrodite is positive for the Y pseudoautosomal boundary. Hum Genet. 1990 Oct;85(6):666–668. doi: 10.1007/BF00193595. [DOI] [PubMed] [Google Scholar]
  15. Koopman P., Gubbay J., Vivian N., Goodfellow P., Lovell-Badge R. Male development of chromosomally female mice transgenic for Sry. Nature. 1991 May 9;351(6322):117–121. doi: 10.1038/351117a0. [DOI] [PubMed] [Google Scholar]
  16. López M., Torres L., Méndez J. P., Cervantes A., Pérez-Palacios G., Erickson R. P., Alfaro G., Kofman-Alfaro S. Clinical traits and molecular findings in 46,XX males. Clin Genet. 1995 Jul;48(1):29–34. doi: 10.1111/j.1399-0004.1995.tb04050.x. [DOI] [PubMed] [Google Scholar]
  17. McElreavey K., Rappaport R., Vilain E., Abbas N., Richaud F., Lortat-Jacob S., Berger R., Le Coniat M., Boucekkine C., Kucheria K. A minority of 46,XX true hermaphrodites are positive for the Y-DNA sequence including SRY. Hum Genet. 1992 Sep-Oct;90(1-2):121–125. doi: 10.1007/BF00210754. [DOI] [PubMed] [Google Scholar]
  18. 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 Acad Sci U S A. 1993 Apr 15;90(8):3368–3372. doi: 10.1073/pnas.90.8.3368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. McElreavey K., Vilain E., Cotinot C., Payen E., Fellous M. Control of sex determination in animals. Eur J Biochem. 1993 Dec 15;218(3):769–783. doi: 10.1111/j.1432-1033.1993.tb18432.x. [DOI] [PubMed] [Google Scholar]
  20. Nakagome Y., Seki S., Fukutani K., Nagafuchi S., Nakahori Y., Tamura T. PCR detection of distal Yp sequences in an XX true hermaphrodite. Am J Med Genet. 1991 Oct 1;41(1):112–114. doi: 10.1002/ajmg.1320410127. [DOI] [PubMed] [Google Scholar]
  21. Numabe H., Nagafuchi S., Nakahori Y., Tamura T., Kiuchi H., Namiki M., Kohda N., Fukushima Y., Fuse H., Kusano M. DNA analyses of XX and XX-hypospadiac males. Hum Genet. 1992 Nov;90(3):211–214. doi: 10.1007/BF00220064. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Schempp W., Müller G., Scherer G., Bohlander S. K., Rommerskirch W., Fraccaro M., Wolf U. Localization of Y chromosome sequences and X chromosomal replication studies in XX males. Hum Genet. 1989 Jan;81(2):144–148. doi: 10.1007/BF00293890. [DOI] [PubMed] [Google Scholar]
  24. Schnee J., Aulehla-Scholz C., Eigel A., Horst J. Hb D Los Angeles (D-Punjab) and Hb Presbyterian: analysis of the defect at the DNA level. Hum Genet. 1990 Mar;84(4):365–367. doi: 10.1007/BF00196236. [DOI] [PubMed] [Google Scholar]
  25. Torres L., López M., Méndez J. P., Canto P., Cervantes A., Alfaro G., Pérez-Palacios G., Erickson R. P., Kofman-Alfaro S. Molecular analysis in true hermaphrodites with different karyotypes and similar phenotypes. Am J Med Genet. 1996 May 17;63(2):348–355. doi: 10.1002/(SICI)1096-8628(19960517)63:2<348::AID-AJMG5>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]
  26. Toublanc J. E., Boucekkine C., Abbas N., Barama D., Vilain E., McElreavey K., Toublanc M., Fellous M. Hormonal and molecular genetic findings in 46,XX subjects with sexual ambiguity and testicular differentiation. Eur J Pediatr. 1993;152 (Suppl 2):S70–S75. doi: 10.1007/BF02125443. [DOI] [PubMed] [Google Scholar]
  27. Vergnaud G., Page D. C., Simmler M. C., Brown L., Rouyer F., Noel B., Botstein D., de la Chapelle A., Weissenbach J. A deletion map of the human Y chromosome based on DNA hybridization. Am J Hum Genet. 1986 Feb;38(2):109–124. [PMC free article] [PubMed] [Google Scholar]
  28. Vollrath D., Foote S., Hilton A., Brown L. G., Beer-Romero P., Bogan J. S., Page D. C. The human Y chromosome: a 43-interval map based on naturally occurring deletions. Science. 1992 Oct 2;258(5079):52–59. doi: 10.1126/science.1439769. [DOI] [PubMed] [Google Scholar]
  29. Wang I., Weil D., Levilliers J., Affara N. A., de la Chapelle A., Petit C. Prevalence and molecular analysis of two hot spots for ectopic recombination leading to XX maleness. Genomics. 1995 Jul 1;28(1):52–58. doi: 10.1006/geno.1995.1105. [DOI] [PubMed] [Google Scholar]
  30. Whitfield L. S., Hawkins T. L., Goodfellow P. N., Sulston J. 41 kilobases of analyzed sequence from the pseudoautosomal and sex-determining regions of the short arm of the human Y chromosome. Genomics. 1995 May 20;27(2):306–311. doi: 10.1006/geno.1995.1047. [DOI] [PubMed] [Google Scholar]
  31. Witt M., Erickson R. P. A rapid method for detection of Y-chromosomal DNA from dried blood specimens by the polymerase chain reaction. Hum Genet. 1989 Jun;82(3):271–274. doi: 10.1007/BF00291168. [DOI] [PubMed] [Google Scholar]
  32. Witt M., Erickson R. P. A rapid method for detection of Y-chromosomal DNA from dried blood specimens by the polymerase chain reaction. Hum Genet. 1991 Mar;86(5):540–540. doi: 10.1007/BF00194654. [DOI] [PubMed] [Google Scholar]
  33. de la Chapelle A. The etiology of maleness in XX men. Hum Genet. 1981;58(1):105–116. doi: 10.1007/BF00284157. [DOI] [PubMed] [Google Scholar]

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