XX male sex reversal with genital abnormalities associated with a de novo SOX3 gene duplication

Sharon Moalem, Riyana Babul-Hirji, Dmitri J. Stavropolous, Diane Wherrett, Darius J. Bägli, Paul Thomas, David Chitayat

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63 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1759-1764
Number of pages6
JournalAmerican Journal of Medical Genetics, Part A
Volume158 A
Issue number7
Publication statusPublished or Issued - Jul 2012
Externally publishedYes


  • Disorders of sex development
  • SOX3
  • XX male sex reversal

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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