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

  • Hum Mol Genet. 2016 Aug 15;25(16):3446-3453. doi: 10.1093/hmg/ddw186.
Anu Bashamboo  1 ,  Patricia A Donohoue  2 ,  Eric Vilain  3 ,  Sandra Rojo  1 ,  Pierre Calvel  1 ,  Sumudu N Seneviratne  4 ,  Federica Buonocore  5 ,  Hayk Barseghyan  6 ,  Nathan Bingham  7 ,  Jill A Rosenfeld  8 ,  Surya Narayan Mulukutla  9 ,  Mahim Jain  8 ,  Lindsay Burrage  8 ,  Shweta Dhar  8 ,  Ashok Balasubramanyam  9 ,  Brendan Lee  8 ,  Members of UDN ,  Marie-Charlotte Dumargne  1 ,  Caroline Eozenou  1 ,  Jenifer P Suntharalingham  5 ,  Ksh de Silva  4 ,  Lin Lin  5 ,  Joelle Bignon-Topalovic  1 ,  Francis Poulat  10 ,  Carlos F Lagos  11 ,  Ken McElreavey  12 ,  John C Achermann  5
Affiliations
  • 1. Human Developmental Genetics, Institut Pasteur, Paris, 75724 France.
  • 2. Department of Pediatrics, Endocrinology & Diabetes, Medical college of Wisconsin, Milwaukee, WI, USA.
  • 3. Departments of Human Genetics, Pediatrics and Urology, David Geffen School of Medicine at UCLA, CA, USA.
  • 4. Department of Pediatrics, Faculty of Medicine, University of Colombo, Colombo 08, Sri Lanka.
  • 5. Genetics & Genomic Medicine, UCL Institute of Child Health, University College London, London, UK.
  • 6. Department of Human Genetics, David Geffen School of Medicine at UCLA, CA, USA.
  • 7. Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Vanderbilt University, Nashville, TN, USA.
  • 8. Department of Molecular and Human Genetics, Baylor College of Medicine, TX.
  • 9. Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston TX, USA.
  • 10. Genetic and Development Department, Institute of Human Genetics, CNRS, Montpellier, France.
  • 11. Department of Endocrinology, Pontificia Universidad Católica de Chile, and Universidad San Sebastián, Santiago, Chile.
  • 12. Human Developmental Genetics, Institut Pasteur, Paris, 75724 France [email protected].
PMID: 27378692 DOI: 10.1093/hmg/ddw186
Abstract

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.