Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9

Nat Commun. 2018 Dec 14;9(1):5319. doi: 10.1038/s41467-018-07784-9.

Abstract

Disorders of sex development (DSDs) are conditions affecting development of the gonads or genitalia. Variants in two key genes, SRY and its target SOX9, are an established cause of 46,XY DSD, but the genetic basis of many DSDs remains unknown. SRY-mediated SOX9 upregulation in the early gonad is crucial for testis development, yet the regulatory elements underlying this have not been identified in humans. Here, we identified four DSD patients with overlapping duplications or deletions upstream of SOX9. Bioinformatic analysis identified three putative enhancers for SOX9 that responded to different combinations of testis-specific regulators. All three enhancers showed synergistic activity and together drive SOX9 in the testis. This is the first study to identify SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY sex reversal, respectively. These enhancers provide a hitherto missing link by which SRY activates SOX9 in humans, and establish SOX9 enhancer mutations as a significant cause of DSD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 46, XX Disorders of Sex Development / genetics
  • Animals
  • Cell Line
  • Clustered Regularly Interspaced Short Palindromic Repeats / genetics
  • Disorder of Sex Development, 46,XY / genetics
  • Disorders of Sex Development / genetics*
  • Female
  • Gene Duplication / genetics*
  • Gene Knockout Techniques
  • Genitalia / metabolism
  • Gonads / metabolism
  • Humans
  • Male
  • Mice
  • Mutation
  • RNA Splicing Factors / metabolism
  • Regulatory Sequences, Nucleic Acid / genetics
  • SOX Transcription Factors / genetics
  • SOX9 Transcription Factor / genetics*
  • SOX9 Transcription Factor / metabolism*
  • Sequence Deletion / genetics*
  • Sex Differentiation
  • Sex-Determining Region Y Protein / genetics*
  • Testis / growth & development
  • Testis / metabolism

Substances

  • RNA Splicing Factors
  • SF1 protein, human
  • SOX Transcription Factors
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • SRY protein, human
  • Sex-Determining Region Y Protein