title: New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression.
abstract: BACKGROUND
  Primary ovarian insufficiency (POI) is a major cause of anovulation and infertility in women. This disease affects 1% of women before 40 years, and several genetic causes have been reported.
  
  
  OBJECTIVE
  The aim of the study was to evaluate the prevalence of NOBOX mutations in a new large cohort of women with POI and to characterize these variants and identify a NOBOX novel target gene.
  
  
  METHODS
  A total of 213 unrelated patients with POI were screened for NOBOX mutations, and luciferase reporter assays were performed for the mutations identified.
  
  
  RESULTS
  We reported 3 novel and 2 recurrent heterozygous missense NOBOX rare variants found in 12 patients but not in 724 alleles from ethnic-matched individual women with occurrence of menopause at a normal age. Their functional impact had been tested on the classic growth differentiation factor-9 (GDF9) promoter and on KIT-L, a new NOBOX target gene. The p.Gly91Thr, p.Gly111Arg, p.Arg117Trp, p.Lys371Thr, and p.Pro619Leu mutations were deleterious for protein function.
  
  
  CONCLUSIONS
  In our series, 5.6% of the patients with POI displayed heterozygous NOBOX mutations. We demonstrate that KIT-L could be now a direct NOBOX target. These findings replicate the high prevalence of the association between the NOBOX rare variants and POI.
authors.affiliation: Inserm U693 (J.B., J.B., A.G.M., J.Y., N.B.), Le Kremlin-Bicêtre, F-94276, France; Université Paris-Sud (J.B., J.Y., N.B.), Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, F-94276, France; Service d'Hormonologie, d'Endocrinologie Moléculaire et Des Maladies Rares (F.R.-B.), Centre De Biologie et Pathologie Est, Université Lyon 1, 69677 Bron, France; Unité de Gynécologie Endocrinienne (A.G.), Université Paris-Descartes, l'Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, 75014 Paris, France; l'Assistance Publique-Hôpitaux de Paris (H.B-G., J.Y., N.B.), Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Le Kremlin-Bicêtre, F-94276, France; Centre d'Aide Médicale à la Procréation (H.B-G.), CHI 94000 Créteil, France; Service de Biochimie et Génétique Moléculaire (K.A., C.B., C.D.), Hôpital Cochin, l'Assistance Publique-Hôpitaux de Paris Université Paris-Descartes, 75006 Paris, France; l'Assistance Publique-Hôpitaux de Paris (J.B., A.G.M.), Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Le Kremlin-Bicêtre, F-94276, France; and Service d'Endocrinologie-Diabète-Nutrition (A.-C.H., B.D.), Centre Hospitalier Universitaire de Reims-Hôpital Robert-Debré, 51092 Reims, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Bouilly
authors.forename: Florence
authors.initials: F
authors.lastname: Roucher-Boulez
authors.forename: Anne
authors.initials: A
authors.lastname: Gompel
authors.forename: Hélène
authors.initials: H
authors.lastname: Bry-Gauillard
authors.forename: Kemal
authors.initials: K
authors.lastname: Azibi
authors.forename: Cherif
authors.initials: C
authors.lastname: Beldjord
authors.forename: Catherine
authors.initials: C
authors.lastname: Dodé
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bouligand
authors.forename: Anne Guiochon
authors.initials: AG
authors.lastname: Mantel
authors.forename: Annie-Claude
authors.initials: AC
authors.lastname: Hécart
authors.forename: Brigitte
authors.initials: B
authors.lastname: Delemer
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Nadine
authors.initials: N
authors.lastname: Binart
mesh_terms: D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D016649:Primary Ovarian Insufficiency / Q000453:epidemiology / Q000235:genetics*; D019089:Stem Cell Factor / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; C506600:NOBOX protein, human; D019089:Stem Cell Factor; D014157:Transcription Factors