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

Brittany Croft, Thomas Ohnesorg, Jacqueline Hewitt, Josephine Bowles, Alexander Quinn, Jacqueline Tan, Vincent Corbin, Emanuele Pelosi, Jocelyn Bergen, Rajini Sreenivasan, Ingrid Knarston, Gorjana Robevska, Dung Chi Vu, John Hutson, Vincent Harley, Katie Ayers, Peter Koopman and Andrew Sinclair ()
Additional contact information
Brittany Croft: Murdoch Children’s Research Institute
Thomas Ohnesorg: Murdoch Children’s Research Institute
Jacqueline Hewitt: Murdoch Children’s Research Institute
Josephine Bowles: University of Queensland
Alexander Quinn: The University of Queensland
Jacqueline Tan: Murdoch Children’s Research Institute
Vincent Corbin: Walter & Eliza Hall Institute of Medical Research
Emanuele Pelosi: The University of Queensland
Jocelyn Bergen: Murdoch Children’s Research Institute
Rajini Sreenivasan: Murdoch Children’s Research Institute
Ingrid Knarston: Murdoch Children’s Research Institute
Gorjana Robevska: Murdoch Children’s Research Institute
Dung Chi Vu: National Children’s Hospital
John Hutson: Murdoch Children’s Research Institute
Vincent Harley: Hudson Institute for Medical Research
Katie Ayers: Murdoch Children’s Research Institute
Peter Koopman: The University of Queensland
Andrew Sinclair: Murdoch Children’s Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07784-9

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