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

• Published in: American journal of human genetics Vol. 102; no. 3; pp. 487 - 493
• Main Authors: Bashamboo, Anu, Eozenou, Caroline, Jorgensen, Anne, Bignon-Topalovic, Joelle, Siffroi, Jean-Pierre, Hyon, Capucine, Tar, Attila, Nagy, Péter, Sólyom, Janos, Halász, Zita, Paye-Jaouen, Annnabel, Lambert, Sophie, Rodriguez-Buritica, David, Bertalan, Rita, Martinerie, Laetitia, Rajpert-De Meyts, Ewa, Achermann, John C., McElreavey, Ken
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2018; Elsevier (Cell Press); Elsevier
• Subjects: 46, XX Disorders of Sex Development - genetics; Amino Acid Sequence; Base Sequence; Child; COUP Transcription Factor II - chemistry; COUP Transcription Factor II - genetics; COUP-TF2; Female; Forkhead Box Protein L2 - metabolism; Frameshift Mutation - genetics; Genetics; Heterozygote; Human genetics; Humans; Life Sciences; Loss of Function Mutation - genetics; Male; new syndrome; NR2F2; nuclear receptor; Ovary - growth & development; Ovary - metabolism; Phenotype; Reproductive Biology; sex determination; Sexual reproduction; testicular DSD; Testis - abnormalities; Testis - growth & development; nuclear receptor; NR2F2; new syndrome; testicular DSD; sex determination; COUP-TF2
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2018.01.021

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.