Justine Bouilly1, Florence Roucher-Boulez, Anne Gompel, Hélène Bry-Gauillard, Kemal Azibi, Cherif Beldjord, Catherine Dodé, Jérôme Bouligand, Anne Guiochon Mantel, Annie-Claude Hécart, Brigitte Delemer, Jacques Young, Nadine Binart. 1. 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.
Abstract
CONTEXT: 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. PATIENTS AND 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.
CONTEXT: 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. PATIENTS AND 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: Amanda Rodriguez; Shawn M Briley; Bethany K Patton; Swamy K Tripurani; Kimal Rajapakshe; Cristian Coarfa; Aleksander Rajkovic; Alexandra Andrieux; Anne Dejean; Stephanie A Pangas Journal: Development Date: 2019-12-02 Impact factor: 6.868
Authors: Monica M França; Mariana F A Funari; Antonio M Lerario; Mirian Y Nishi; Carmem C Pita; Eveline G P Fontenele; Berenice B Mendonca Journal: Endocrine Date: 2017-10-24 Impact factor: 3.633
Authors: JoAnne S Richards; Yi A Ren; Nicholes Candelaria; Jaye E Adams; Aleksandar Rajkovic Journal: Endocr Rev Date: 2018-02-01 Impact factor: 19.871
Authors: Sarah Eskenazi; Anne Bachelot; Justine Hugon-Rodin; Genevieve Plu-Bureau; Anne Gompel; Sophie Catteau-Jonard; Denise Molina-Gomes; Didier Dewailly; Catherine Dodé; Sophie Christin-Maitre; Philippe Touraine Journal: J Endocr Soc Date: 2021-03-01