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Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children
- Source :
- 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⟩
- Publication Year :
- 2018
- Publisher :
- HAL CCSD, 2018.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 00029297 and 15376605
- Database :
- OpenAIRE
- Journal :
- 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⟩
- Accession number :
- edsair.doi.dedup.....9e91d6a53f3d8867c6d02692f0689a27