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

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

Author information

1
Murdoch Children's Research Institute, Melbourne, 3052, VIC, Australia.
2
Department of Molecular & Translational Science, Monash University, Clayton, 3800, VIC, Australia.
3
Department of Paediatrics, The University of Melbourne, Melbourne, 3010, VIC, Australia.
4
School of Bioscience, University of Melbourne, Melbourne, 3010, VIC, Australia.
5
Department of Paediatric Urology, Monash Children's Hospital, Clayton, 3168, VIC, Australia.
6
School of Biomedical Sciences, University of Queensland, Brisbane, 4072, QLD, Australia.
7
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia.
8
Bioinformatics Division, Walter & Eliza Hall Institute of Medical Research, Melbourne, 3052, VIC, Australia.
9
Hudson Institute for Medical Research, Clayton, 3168, VIC, Australia.
10
Department of Medical Genetics, Metabolism & Endocrinology, National Children's Hospital, Hanoi, Vietnam.
11
Department of Urology, Royal Children's Hospital, Melbourne, 3052, VIC, Australia.
12
Murdoch Children's Research Institute, Melbourne, 3052, VIC, Australia. Andrew.sinclair@mcri.edu.au.
13
Department of Paediatrics, The University of Melbourne, Melbourne, 3010, VIC, Australia. Andrew.sinclair@mcri.edu.au.

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.

PMID:
30552336
PMCID:
PMC6293998
DOI:
10.1038/s41467-018-07784-9
[Indexed for MEDLINE]
Free PMC Article

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