This is the first demonstration of altered SOX3 expression in an individual with XX male sex reversal and suggests that SOX3 can substitute for SRY to initiate male development in humans.
To explore how a 148 kb RevSex duplication could have turned on gonadal SOX9 expression in the absence of SRY in an XX-male, we examined the chromatin landscape in primary skin fibroblast cultures from the index, his RevSex duplication-carrier father and six controls.
These data provide additional evidence that SOX3 gain-of-function in the XX bipotential gonad causes XX male sex reversal and further support the hypothesis that SOX3 is the evolutionary antecedent of SRY.
The phenotype of XX males depends on the presence of SRY (sex-determining region Y) and the level of X inactivation at which SRY-negative patients are generally rarely observed.
Using fluorescence in situ hybridization (FISH) or PCR, it was possible to detect the transfer of Yp fragments including SRY gene to the terminal part of X chromosome in the majority of XX males.
Abnormal recombination between the X and Y chromosomes during meiosis, occurring outside the pseudoautosomal region, can result in translocation of the SRY gene from the Y to the X chromosome, and consequently in abnormal sexual differentiation, such as the development of 46,XX males or true hermaphroditism.
True hermaphrodites without a Y chromosome and XX males represent a sex determination error in which testicular tissue develops despite the absence of the SRY gene.
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.
However, the existence of total or partial sex reversal in 46,XX males with genetic mutations not linked to the Y chromosome suggests that several autosomal genes acting in association with SRY may contribute to normal development of the male phenotype.
Our observation is in agreement with the view that 46 XX male subjects diagnosed at peripubertal age with the SRY gene in the genome have a good prognosis regarding growth and development, but the principal problem of these patients is infertility.