NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development

Dorien Baetens, Hans Stoop, Frank Peelman, Anne-Laure Todeschini, Toon Rosseel, Frauke Coppieters, Reiner A Veitia, Leendert H J Looijenga, Elfride De Baere, Martine Cools

Research output: Contribution to journalArticlepeer-review

84 Citations (Scopus)


PURPOSE: 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).

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

Original languageEnglish
Pages (from-to)367-376
Number of pages10
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Issue number4
Publication statusPublished - Apr 2017
Externally publishedYes


  • DNA-Binding Proteins/genetics
  • Female
  • Gene Expression Profiling/methods
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Male
  • Models, Molecular
  • Mutation, Missense
  • Nuclear Proteins/genetics
  • Ovary/metabolism
  • Ovotesticular Disorders of Sex Development/genetics
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, RNA/methods
  • Steroidogenic Factor 1/chemistry
  • Testis/metabolism
  • Transcription Factors/genetics
  • Up-Regulation
  • Whole Exome Sequencing/methods
  • Young Adult


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