Differentiation of the bipotential gonad into testis is initiated by the Y 
chromosome-linked gene SRY (Sex-determining Region Y) through upregulation of 
its autosomal direct target gene SOX9 (Sry-related HMG box-containing gene 9). 
Sequence and chromosome homology studies have shown that SRY most probably 
evolved from SOX3, which in humans is located at Xq27.1. Mutations causing SOX3 
loss-of-function do not affect the sex determination in mice or humans. However, 
transgenic mouse studies have shown that ectopic expression of Sox3 in the 
bipotential gonad results in upregulation of Sox9, resulting in testicular 
induction and XX male sex reversal. However, the mechanism by which these 
rearrangements cause sex reversal and the frequency with which they are 
associated with disorders of sex development remains unclear. Rearrangements of 
the SOX3 locus were identified recently in three cases of human XX male sex 
reversal. We report on a case of XX male sex reversal associated with a novel de 
novo duplication of the SOX3 gene. 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.