title: A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.
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.
authors.affiliation: Human Developmental Genetics, Institut Pasteur, Paris, 75724 France.
authors.forename: Anu
authors.initials: A
authors.lastname: Bashamboo
authors.affiliation: Department of Pediatrics, Endocrinology & Diabetes, Medical college of Wisconsin, Milwaukee, WI, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Donohoue
authors.affiliation: Departments of Human Genetics, Pediatrics and Urology, David Geffen School of Medicine at UCLA, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
authors.affiliation: Human Developmental Genetics, Institut Pasteur, Paris, 75724 France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rojo
authors.affiliation: Human Developmental Genetics, Institut Pasteur, Paris, 75724 France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Calvel
authors.affiliation: Department of Pediatrics, Faculty of Medicine, University of Colombo, Colombo 08, Sri Lanka.
authors.forename: Sumudu N
authors.initials: SN
authors.lastname: Seneviratne
authors.affiliation: Genetics & Genomic Medicine, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Federica
authors.initials: F
authors.lastname: Buonocore
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, CA, USA.
authors.forename: Hayk
authors.initials: H
authors.lastname: Barseghyan
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Vanderbilt University, Nashville, TN, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Bingham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, TX.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston TX, USA.
authors.forename: Surya Narayan
authors.initials: SN
authors.lastname: Mulukutla
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, TX.
authors.forename: Mahim
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, TX.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Burrage
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, TX.
authors.forename: Shweta
authors.initials: S
authors.lastname: Dhar
authors.affiliation: Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston TX, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Balasubramanyam
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, TX.
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.affiliation: Human Developmental Genetics, Institut Pasteur, Paris, 75724 France.
authors.forename: Marie-Charlotte
authors.initials: MC
authors.lastname: Dumargne
authors.affiliation: Human Developmental Genetics, Institut Pasteur, Paris, 75724 France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Eozenou
authors.affiliation: Genetics & Genomic Medicine, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Jenifer P
authors.initials: JP
authors.lastname: Suntharalingham
authors.affiliation: Department of Pediatrics, Faculty of Medicine, University of Colombo, Colombo 08, Sri Lanka.
authors.forename: Ksh
authors.initials: K
authors.lastname: de Silva
authors.affiliation: Genetics & Genomic Medicine, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: Human Developmental Genetics, Institut Pasteur, Paris, 75724 France.
authors.forename: Joelle
authors.initials: J
authors.lastname: Bignon-Topalovic
authors.affiliation: Genetic and Development Department, Institute of Human Genetics, CNRS, Montpellier, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Poulat
authors.affiliation: Department of Endocrinology, Pontificia Universidad Católica de Chile, and Universidad San Sebastián, Santiago, Chile.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Lagos
authors.affiliation: Human Developmental Genetics, Institut Pasteur, Paris, 75724 France kenmce@pasteur.fr.
authors.forename: Ken
authors.initials: K
authors.lastname: McElreavey
authors.affiliation: Genetics & Genomic Medicine, UCL Institute of Child Health, University College London, London, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
mesh_terms: D000328:Adult; D013734:Androgen-Insensitivity Syndrome / Q000235:genetics / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics* / Q000473:pathology; D005260:Female; D006066:Gonads / Q000254:growth & development / Q000473:pathology; D006801:Humans; D059785:Karyotype; D008297:Male; D020125:Mutation, Missense; D010053:Ovary / Q000254:growth & development / Q000473:pathology; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000235:genetics* / Q000473:pathology; D019849:Sex Determination Processes; D046468:Sexual Development / Q000235:genetics*; D054339:Steroidogenic Factor 1 / Q000235:genetics*; D013737:Testis / Q000254:growth & development / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1