title: BMP15 "knockout-like" effect in familial premature ovarian insufficiency with persistent ovarian reserve.
abstract: Premature ovarian insufficiency (POI) affects 1% to 2% of women under 40 years. Bone morphogenetic protein 15 (BMP15) variants have been described in POI. We studied a family with 2 sisters compound heterozygous for deletions in the BMP15 gene on chromosome Xp11.22 yielding a human "knockout-like" effect: a c.151_152delGA deletion yielded a p.Glu51IlefsTer27 mutation transmitted by the hemizygous father and a c.189_198delAGGGCATTCAinsTG deletion/insertion yielded a p.Glu64AlafsTer12 mutation transmitted by the heterozygous mother. Both deletions resulted in frameshifts with premature stop codons at positions 78 and 76 in the proregion, precluding mature BMP15 production. One sister had primary amenorrhea and the other primo-secondary amenorrhea. No bone abnormality was observed. Despite streak ovaries devoid of follicles on ultrasonography, anti-Mullerian hormone (AMH) levels were low but detectable suggesting the presence of growing follicles. Five years later, AMH was undetectable in both sisters, 1 had received an egg donation. BMP15 did not seem critical for follicles to enter the growth phase. Genetic counselling should be performed and fertility preservation discussed before progressive loss of follicular reserve. The fertile heterozygous mother did not support previous reports of BMP15 haploinsufficiency and gene dosage in humans, as in bovine species. The hemizygous brother had asthenozoospermia, consistent with previous observations in bulls with a variant BMP15.
authors.affiliation: Department of Endocrinology (AM), Chambery Hospital, Chambery, France.
authors.forename: A
authors.initials: A
authors.lastname: Mayer
authors.affiliation: Faculté de Médecine Paris Sud, Université Paris Sud, Université Paris Saclay, Le Kremlin Bicêtre, France.
authors.forename: B
authors.initials: B
authors.lastname: Fouquet
authors.affiliation: INSERM U1060 CARMEN Institute, Fédération d'endocrinologie Est (MP), Université de Lyon 1, Oullins, France.
authors.forename: M
authors.initials: M
authors.lastname: Pugeat
authors.affiliation: Faculté de Médecine Paris Sud, Université Paris Sud, Université Paris Saclay, Le Kremlin Bicêtre, France.
authors.forename: M
authors.identifier: http://orcid.org/0000-0002-5379-8859
authors.initials: M
authors.lastname: Misrahi
mesh_terms: D000328:Adult; D000568:Amenorrhea / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D055430:Bone Morphogenetic Protein 15 / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics; D005260:Female; D055786:Gene Knockout Techniques; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D006080:Ovarian Follicle / Q000254:growth & development / Q000473:pathology; D065851:Ovarian Reserve / Q000235:genetics* / Q000502:physiology; D016649:Primary Ovarian Insufficiency / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D017384:Sequence Deletion / Q000235:genetics
chemical_list: C525901:BMP15 protein, human; D055430:Bone Morphogenetic Protein 15; D018389:Codon, Nonsense
keywords: 
  BMP15
  ; deletion; fertility preservation; gene; haploinsufficiency; knockout; male; mutation; premature ovarian insufficiency