title: NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.
abstract: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD).
  
  
  
  Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq.
  
  
  
  We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed.
  
  
  
  We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad.Genet Med 19 4, 367-376.
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Dorien
authors.initials: D
authors.lastname: Baetens
authors.affiliation: Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Hans
authors.identifier: 0000-0002-2475-6991
authors.initials: H
authors.lastname: Stoop
authors.affiliation: Flanders Institute for Biotechnology (VIB), Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Peelman
authors.affiliation: Molecular Oncology and Pathology, Institut Jacques Monod, France; Université Paris Diderot, Paris VII, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Todeschini
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Toon
authors.identifier: 0000-0002-8155-3197
authors.initials: T
authors.lastname: Rosseel
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Frauke
authors.initials: F
authors.lastname: Coppieters
authors.affiliation: Molecular Oncology and Pathology, Institut Jacques Monod, France; Université Paris Diderot, Paris VII, France.
authors.forename: Reiner A
authors.identifier: 0000-0002-4100-2681
authors.initials: RA
authors.lastname: Veitia
authors.affiliation: Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Leendert H J
authors.identifier: 0000-0002-8146-1911
authors.initials: LH
authors.lastname: Looijenga
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Elfride
authors.identifier: 0000-0002-9552-4899
authors.initials: E
authors.lastname: De Baere
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University Hospital and Ghent University, Ghent, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Cools
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D010053:Ovary / Q000378:metabolism; D050090:Ovotesticular Disorders of Sex Development / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017423:Sequence Analysis, RNA / Q000379:methods*; D054339:Steroidogenic Factor 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation; D000073359:Exome Sequencing / Q000379:methods*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C528016:MAMLD1 protein, human; C515057:NR5A1 protein, human; D009687:Nuclear Proteins; D054339:Steroidogenic Factor 1; D014157:Transcription Factors