Summary
Cytogenetic and molecular studies in patients with abnormalities of sex determination have been the key to the isolation and investigation of candidates for the primary testis determining factor (TDF). A gene, SRY, isolated from the sex determining region of the Y chromosome within 5 kilobases of the pairing segment boundary, has been characterized recently which fulfils the expectations of TDF. It is expressed in the embryonic gonads at the critical time of differentiation; it is highly conserved among mammals; it has the structure of a transcription regulator; and mutations within its conserved domain are found in 10% of sex-reversed XY females. The murine homologue of this gene has been shown to cause sex reversal in XX embryos following injection of a 14 kb DNA fragment containing SRY into fertilized eggs. However, most XX true hermaphrodites and a proportion of XX sex-reversed males lack SRY despite the presence of testicular differentiation. It is postulated that the constitutive activation of an X-linked gene, TDF-2, normally regulated by SRY, is responsible for male differentiation in these cases. The female phenotype of XY individuals with duplications of Xp may be the result or deletion of disruption of TDF-2.
Similar content being viewed by others
References
Bernstein R, Jenkins T, Dawson B et al (1980) Female phenotype and multiple abnormalities in sibs with a Y chromosome and partial X chromosome duplication.J Med Genet 17: 291–300.
Berta P, Hawkins JR, Sinclair AH et al (1990) Genetic evidence equating SRY and the testis determining factor.Nature 348: 448–450.
Connor JM, Ferguson-Smith MA (1990)Essential Medical Genetics, 3rd edn. Oxford: Blackwell Scientific Publications.
Ferguson-Smith MA (1966) X-Y chromosomal interchange in the aetiology of true hermaphroditism and of XX Klinefelter's syndrome.Lancet 2: 475–476.
Ferguson-Smith MA, Affara NA (1988) Accidental X-Y recombination and the aetiology of XX males and true hermaphrodites.Phil Trans R Soc Lond B 322: 133–144.
Ferguson-Smith MA, Affara NA, Magenis RE (1987) Ordering of Y specific sequences by deletion mapping and analysis of X-Y interchange males and females.Development 101 (Suppl.): 41–50.
Ferguson-Smith MA, Cooke A, Affara NA, Boyd E, Tolmie JL (1990) Genotype-phenotype correlations in XX males and their bearing on current theories of sex determination.Hum Genet 84: 198–202.
Gartler SM, Waxman SM, Giblett E (1962) An XX/XY human hermaphrodite resulting from double fertilisation.Proc Natl Acad Sci USA 48: 332–335.
Guellaen G, Casanova M, Bishop C et al (1984) Human XX males with Y single copy DNA fragments.Nature 307: 172–173.
Hodgkin J (1990) Sex determination compared inDrosophila andCaenorhabditis.Nature 344: 721–728.
Jäger RJ, Anvret M, Hall K, Scherer G (1990a) A human XY female with a frame shift mutation in the candidate testis determining gene SRY.Nature 348: 452–454.
Jäger RJ, Ebensperger C, Fraccaro M, Scherer G (1990b) A XFY-negative 46,XX true hermaphrodite is positive for the Y pseudoautosomal boundary.Hum Genet 85: 666–668.
Jones KW, Singh L (1981) Conserved repeated DNA sequences in vertebrate sex chromosomes.Hum Genet 58: 46–53.
Jost A (1947) Recherches sur la differenciation sexuelle de l'embryon de lapin. III. Role des gonades foetales dans la differentiation sexuelle somatique.Arch Anat Micr Morphol Exp 36: 271.
Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R (1991) Male development of chromosomally female mice transgenic for Sry.Nature 351: 117–121.
McLaren A (1988) Sex determination in mammals.Trends Genet 4: 153–157.
Page DC, Mosher R, Simpson EM et al (1987) The sex determining region of the human Y chromosome encodes a finger protein.Cell 51: 1091–1104.
Palmer MS, Sinclair AH, Berta P et al (1989) Genetic evidence that ZFY is not the testisdetermining factor.Nature 342: 937–939.
Scherer G, Schempp W, Baccichetti C et al (1989) Duplication of an Xp segment that includes the ZFX locus causes sex inversion in man.Hum Genet 81: 291–294.
Simpson E, Chandler P, Goulmy E, Disteche CM, Ferguson-Smith MA, Page DC (1987) Separation of the genetic loci for the H-Y antigen and for testis determination on human Y chromosome.Nature 326: 876–878.
Sinclair AH, Berta P, Palmer MS et al (1990) A gene from the human sex determining region encodes a protein with homology to a conserved DNA-binding motif.Nature 346: 244.
Tarkowski AJ (1964) True hermaphroditism in chimaeric mice.J Embryol Exp Morphol 12: 735–757.
Wachtel S, Ohno S, Koo G, Boyse EA (1975) Possible role for H-Y antigen in the primary determination of sex.Nature 257: 235–236.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ferguson-Smith, M.A. Abnormalities of human sex determination. J Inherit Metab Dis 15, 518–525 (1992). https://doi.org/10.1007/BF01799610
Issue Date:
DOI: https://doi.org/10.1007/BF01799610