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

Author

Listed:
  • Brittany Croft

    (Murdoch Children’s Research Institute
    Monash University)

  • Thomas Ohnesorg

    (Murdoch Children’s Research Institute
    The University of Melbourne)

  • Jacqueline Hewitt

    (Murdoch Children’s Research Institute
    University of Melbourne
    Monash Children’s Hospital)

  • Josephine Bowles

    (University of Queensland
    The 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
    Hudson Institute for Medical Research)

  • Ingrid Knarston

    (Murdoch Children’s Research Institute
    The University of Melbourne)

  • Gorjana Robevska

    (Murdoch Children’s Research Institute)

  • Dung Chi Vu

    (National Children’s Hospital)

  • John Hutson

    (Murdoch Children’s Research Institute
    The University of Melbourne
    Royal Children’s Hospital)

  • Vincent Harley

    (Hudson Institute for Medical Research)

  • Katie Ayers

    (Murdoch Children’s Research Institute
    The University of Melbourne)

  • Peter Koopman

    (The University of Queensland)

  • Andrew Sinclair

    (Murdoch Children’s Research Institute
    The University of Melbourne)

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.

Suggested Citation

  • Brittany Croft & Thomas Ohnesorg & Jacqueline Hewitt & Josephine Bowles & Alexander Quinn & Jacqueline Tan & Vincent Corbin & Emanuele Pelosi & Jocelyn Bergen & Rajini Sreenivasan & Ingrid Knarston & , 2018. "Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07784-9
    DOI: 10.1038/s41467-018-07784-9
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    Cited by:

    1. Denis Houzelstein & Caroline Eozenou & Carlos F. Lagos & Maëva Elzaiat & Joelle Bignon-Topalovic & Inma Gonzalez & Vincent Laville & Laurène Schlick & Somboon Wankanit & Prochi Madon & Jyotsna Kirtane, 2024. "A conserved NR5A1-responsive enhancer regulates SRY in testis-determination," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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