Print page Print page
Switch language
Rigshospitalet - a part of Copenhagen University Hospital

Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Recurrent, Activating Variants in the Receptor Tyrosine Kinase DDR2 Cause Warburg-Cinotti Syndrome

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Anu Bashamboo
  • Caroline Eozenou
  • Anne Jorgensen
  • Joelle Bignon-Topalovic
  • Jean-Pierre Siffroi
  • Capucine Hyon
  • Attila Tar
  • Péter Nagy
  • Janos Sólyom
  • Zita Halász
  • Annnabel Paye-Jaouen
  • Sophie Lambert
  • David Rodriguez-Buritica
  • Rita Bertalan
  • Laetitia Martinerie
  • Ewa Rajpert-De Meyts
  • John C Achermann
  • Ken McElreavey
View graph of relations

Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs∗75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs∗77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 × 10-8). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human "pro-ovary" and "anti-testis" sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Issue number3
Pages (from-to)487-93
Publication statusPublished - 2018

    Research areas

  • Journal Article

ID: 52793280