title: Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort.
abstract: Primary ovarian insufficiency (POI) is a disorder associated with female infertility, which affects approximately 1% of women under 40 years of age. A genetic component has been suggested as one possible cause of the majority of cases of nonsyndromic forms. Newborn Ovary Homeobox (NOBOX) is an ovary-specific gene, playing a critical role in ovary in mice, as its absence leads to sterility mimicking a POI. In this study, we sequenced NOBOX in a cohort of 178 women with idiopathic POI. Among 19 identified variations, we described one nonsense (c.907C>T/p.R303X) and four missense (c.271G>T/p.G91W, c.349C>T/p.R117W, c.1025G>C/p.S342T, and c.1048G>T/p.V350L) NOBOX heterozygous mutations in 12 patients. We reproduced each of the five mutations and tested their effects on the signaling activity in transfected cells. We demonstrated that these mutations compromised the ability of the proteins to bind to and transactivate the well-known growth differentiation factor 9 (GDF9) promoter. The pattern of our findings suggests that the genetic mechanism in humans responsible for POI in women involves haploinsufficiency rather than dominant negative gene action. The identification, characterization, and the very high 6.2% prevalence of these new mutations in POI patients suggest considering NOBOX as the first autosomal candidate gene involved in this syndrome.
authors.affiliation: Univ Paris-Sud, Faculté de Médecine Paris-Sud, UMR-S693, Kremlin-Bicêtre, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Bouilly
authors.forename: Anne
authors.initials: A
authors.lastname: Bachelot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Broutin
authors.forename: Philippe
authors.initials: P
authors.lastname: Touraine
authors.forename: Nadine
authors.initials: N
authors.lastname: Binart
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D023061:Gene Order; D057809:HEK293 Cells; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D015995:Prevalence; D016649:Primary Ovarian Insufficiency / Q000453:epidemiology / Q000235:genetics*; D011487:Protein Conformation; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C506600:NOBOX protein, human; D014157:Transcription Factors