title: Variants of the BMP15 gene in a cohort of patients with premature ovarian failure.
abstract: BACKGROUND
  Bone morphogenetic protein 15 (BMP15) is an oocyte-derived growth factor acting as a major player in follicle differentiation in mammals. Mutations in the BMP15 gene, some of which lead to defective secretion of bioactive dimers, have been associated with premature ovarian failure (POF) in humans.
  
  
  METHODS
  Fifty patients diagnosed with POF with a normal karyotype were included in the study. After DNA extraction and amplification by PCR, the entire coding sequence and intron-exon junctions of BMP15 gene were analysed in the cohort of POF patients and in a control group of 214 patients.
  
  
  RESULTS
  Nine variants of the BMP15 gene including six missense substitutions and one insertion of three nucleotides were identified in the POF group. Three of them were previously described as single nucleotide polymorphisms and were also found in the control group. Two variants (H81R and G199R) have not been previously described and were not identified among controls but were not predicted to be deleterious. One variant (A180T) was identified among two POF cases, and also in two controls. One variant (F194S), predicted as potentially deleterious, was identified for the first time in a POF patient but also identified in one control. One variant (L148P), potentially deleterious, previously reported in POF patients, was identified for the first time among controls. The variant 788insTCT, previously identified among POF patients, probably has a low biological impact as it was also found in control patients and is a common polymorphism in sub-Saharan African populations.
  
  
  CONCLUSIONS
  Various missense variants of the BMP15 gene were identified among patients with POF. For most variants, the impact of the amino-acid substitution on the protein structure and function was predicted to be low. The two variants predicted as potentially deleterious were also identified among controls and could be considered as rare polymorphisms. Although some of these variants could contribute to the development of POF in a complex manner, the demonstration of their role in the pathogenesis of POF requires additional functional studies.
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Faculté de Médecine, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Tiotiu
authors.forename: B
authors.initials: B
authors.lastname: Alvaro Mercadal
authors.forename: R
authors.initials: R
authors.lastname: Imbert
authors.forename: J
authors.initials: J
authors.lastname: Verbist
authors.forename: I
authors.initials: I
authors.lastname: Demeestere
authors.forename: A
authors.initials: A
authors.lastname: De Leener
authors.forename: Y
authors.initials: Y
authors.lastname: Englert
authors.forename: G
authors.initials: G
authors.lastname: Vassart
authors.forename: S
authors.initials: S
authors.lastname: Costagliola
authors.forename: A
authors.initials: A
authors.lastname: Delbaere
mesh_terms: D000328:Adult; D000483:Alleles; D000568:Amenorrhea / Q000235:genetics*; D055430:Bone Morphogenetic Protein 15 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011795:Surveys and Questionnaires
chemical_list: C525901:BMP15 protein, human; D055430:Bone Morphogenetic Protein 15