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Hum Mol Genet. 2016 Aug 15;25(16):3446-3453. doi: 10.1093/hmg/ddw186. Epub 2016 Jul 4.

A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.

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Human Developmental Genetics, Institut Pasteur, Paris, 75724 France.
Department of Pediatrics, Endocrinology & Diabetes, Medical college of Wisconsin, Milwaukee, WI, USA.
Departments of Human Genetics, Pediatrics and Urology, David Geffen School of Medicine at UCLA, CA, USA.
Department of Pediatrics, Faculty of Medicine, University of Colombo, Colombo 08, Sri Lanka.
Genetics & Genomic Medicine, UCL Institute of Child Health, University College London, London, UK.
Department of Human Genetics, David Geffen School of Medicine at UCLA, CA, USA.
Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Vanderbilt University, Nashville, TN, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, TX.
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston TX, USA.
Genetic and Development Department, Institute of Human Genetics, CNRS, Montpellier, France.
Department of Endocrinology, Pontificia Universidad Católica de Chile, and Universidad San Sebastián, Santiago, Chile.
Human Developmental Genetics, Institut Pasteur, Paris, 75724 France


Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying this NR5A1 mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans.

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