title: Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure.
abstract: BACKGROUND
  Premature ovarian failure (POF) is a cause of female infertility characterized by primary (PA) or secondary amenorrhea (SA) and elevated gonadotropins. The pathogenesis is unknown in most cases. We recently reported two sisters with PA carrying a heterozygous mutation of BMP15 gene (locus Xp11.2), but the prevalence of BMP15 variations in the POF population is unknown.
  
  
  OBJECTIVE
  The objective of the study was to verify the involvement of BMP15 variations in a large POF population.
  
  
  METHODS
  Genetic screening of 166 unrelated patients with idiopathic POF (25 PA, 141 SA) and controls (group A: 95 women with menopause beyond 50 yr of age; group B: 86 women and 30 men from the general population) of Caucasian origin.
  
  
  RESULTS
  Investigation revealed four heterozygous variations affecting the proregion of BMP15. The previously reported p.Y235C mutation occurred in one and three novel variants in eight patients: two missense alterations (p.R68W in one case, p.A180T in five) and one insertion (p.262insLeu) in two cases. The p.262insLeu was found in five controls of group A, thus diminishing its potential biological impact, whereas the other three variants were not present in any of the controls. All new mutations were found in SA cases.
  
  
  CONCLUSIONS
  We describe the significant association of heterozygous BMP15 gene variants with the POF phenotype in humans (seven of 166 patients: 4.2%; P < 0.003 vs. controls). These findings are consistent with the critical role played by BMP15 in human folliculogenesis.
authors.affiliation: Department of Medical Sciences, University of Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Di Pasquale
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rossetti
authors.forename: Anna
authors.initials: A
authors.lastname: Marozzi
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bodega
authors.forename: Stefano
authors.initials: S
authors.lastname: Borgato
authors.forename: Luciano
authors.initials: L
authors.lastname: Cavallo
authors.forename: Silvia
authors.initials: S
authors.lastname: Einaudi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Radetti
authors.forename: Gianni
authors.initials: G
authors.lastname: Russo
authors.forename: Michele
authors.initials: M
authors.lastname: Sacco
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wasniewska
authors.forename: Trevor
authors.initials: T
authors.lastname: Cole
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Nelson
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
mesh_terms: D000293:Adolescent; D000328:Adult; D055430:Bone Morphogenetic Protein 15; D002648:Child; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D055429:Growth Differentiation Factor 9; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007438:Introns / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D016649:Primary Ovarian Insufficiency / Q000235:genetics*
chemical_list: C525901:BMP15 protein, human; D055430:Bone Morphogenetic Protein 15; C525897:GDF9 protein, human; D055429:Growth Differentiation Factor 9; D036341:Intercellular Signaling Peptides and Proteins