Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children
| Autor: | Caroline Eozenou, David Rodriguez-Buritica, Zita Halász, Jean-Pierre Siffroi, Joelle Bignon-Topalovic, Anne Jorgensen, Sophie Lambert, Rajpert-De Meyts E, János Sólyom, Anu Bashamboo, Ken McElreavey, Paye-Jaouen A, Rita Bertalan, Attila Tar, Capucine Hyon, John C. Achermann, Peter Nagy, Laetitia Martinerie |
|---|---|
| Přispěvatelé: | Génétique du développement humain, Institut Pasteur [Paris], Department of Growth and Reproduction [Rigshospitalet], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pál Heim Children's Hospital = Heim Pál Gyermekkórház [Budapest], First Department of Pathology and Experimental Cancer Research, Semmelweis University [Budapest], Chirurgie viscérale et urologie pédiatriques [AP-HP Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Endocrinologie et Diabétologie Pédiatriques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Copenhagen University Hospital, Institute of Child Health [London], University College of London [London] (UCL), A.B. is funded in part by the program Actions Concertees Interpasteuriennes (ACIP) and a research grant from the European Society of Pediatric Endocrinology. A.B. and K.McE. are funded by a research grant from the EuroDSD in the European Community’s Seventh Framework Programme FP7/2007-2013 under grant agreement no. 201444 as well as grant no. 295097 as part of the EU call FP7-INCO-2011-6. J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science (grant 098513/Z/12/Z, 209328/Z/17/Z) with research support from Great Ormond Street Hospital Children's Charity (grant V2518) and the NIHR GOSH BRC (IS-BRC-1215-20012)., This work is supported by the COST Action DSDnet BM1303., This work was funded by the Agence Nationale de la Recherche (Laboratoire d’Excellence Revive, Investissement d’Avenir, ANR-10-LABX-73)., The authors wish to thank Dr. Etienne Patin for comments on the manuscript., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), European Project: 201444,EC:FP7:HEALTH,FP7-HEALTH-2007-A,EURODSD(2008), European Project: 295097,EC:FP7:INCO,FP7-INCO-2011-6,GM_NCD_IN_CO(2011), Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Forkhead Box Protein L2
Male 0301 basic medicine new syndrome 46 XX Disorders of Sex Development [SDV]Life Sciences [q-bio] MESH: 46 XX Disorders of Sex Development / genetics sex determination MESH: Amino Acid Sequence MESH: Loss of Function Mutation / genetics MESH: Base Sequence Bioinformatics medicine.disease_cause COUP Transcription Factor II 0302 clinical medicine Loss of Function Mutation MESH: Ovary / growth & development MESH: Child Testis MESH: Testis / growth & development nuclear receptor Child Frameshift Mutation Exome Genetics (clinical) MESH: Heterozygote 0303 health sciences education.field_of_study Mutation MESH: Testis / abnormalities MESH: COUP Transcription Factor II / genetics Cell biology Phenotype medicine.anatomical_structure 030220 oncology & carcinogenesis Female medicine.symptom Heterozygote medicine.drug_class Population Ovary Biology MESH: COUP Transcription Factor II / chemistry MESH: Phenotype Frameshift mutation [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction 03 medical and health sciences MESH: Forkhead Box Protein L2 / metabolism Report Genetics medicine Humans Amino Acid Sequence education testicular DSD Loss function 030304 developmental biology MESH: Humans Base Sequence Virilization MESH: Frameshift Mutation / genetics Androgen MESH: Ovary / metabolism NR2F2 MESH: Male 030104 developmental biology Nuclear receptor [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics COUP-TF2 Cardiac defects MESH: Female |
| Zdroj: | American Journal of Human Genetics American Journal of Human Genetics, Elsevier (Cell Press), 2018, 102 (3), pp.487-493. ⟨10.1016/j.ajhg.2018.01.021⟩ American Journal of Human Genetics, 2018, 102 (3), pp.487-493. ⟨10.1016/j.ajhg.2018.01.021⟩ |
| ISSN: | 0002-9297 1537-6605 |
| DOI: | 10.1016/j.ajhg.2018.01.021⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|