Abnormalities of human sex determination.

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.