title: Missense mutations in the BMP15 gene are associated with ovarian failure.
abstract: Premature ovarian failure (POF) is an unexplained amenorrhoea (>6 months) with raised levels of gonadotropins (FSH>40 U/L) occurring before the age of 40 years. Recent studies have elucidated the role of oocyte derived growth factors (BMP15 and GDF9) in maintenance of folliculogenesis, granulosa cell (GC) proliferation and overall fertility. Our recently published work showed presence of two rare missense variants in the GDF9 gene associated with ovarian failure (Dixit et al. 2005, Menopause 12:749-754). The present case-control study has been structured to establish the role of BMP15 germline status associated with ovarian failure. Sequence analysis of the coding region of the BMP15 gene was carried out in a cohort of women with POF (n=133), primary amenorrhoea (n=60), and secondary amenorrhoea (n=9) compared with control females (n=197). This study revealed a total of 18 germline variants in the coding region of BMP15 gene, including 16 novel variants. These novel variants include one intronic variant, one 3' flanking variant, one silent variant, and 13 missense variants. Eleven missense variants were present only in cases with complete absence in the control females. The remaining two missense variants viz. c.308A>G (p.Asn103Ser) and c.788_789insTCT (p.Leu263_Arg264insLeu) were present both in the cases and in the controls. The c.788_789insTCT variant was significantly higher in primary amenorrhoea cases than in the controls (Fisher's exact test, P=0.034). Three frequent variants c.-9C>G, c.308A>G, and c.852C>T were chosen for haplotyping. The haplotype G-G-C was found to be significantly associated with ovarian failure (P=0.0075). In a nutshell, the BMP15 gene is highly associated with etiology of ovarian failure.
authors.affiliation: Centre for Cellular and Molecular Biology, Uppal Road, 500007, Hyderabad, AP, India.
authors.forename: Hridesh
authors.initials: H
authors.lastname: Dixit
authors.forename: Lakshmi K
authors.initials: LK
authors.lastname: Rao
authors.forename: Venkata V
authors.initials: VV
authors.lastname: Padmalatha
authors.forename: Murthy
authors.initials: M
authors.lastname: Kanakavalli
authors.forename: Mamata
authors.initials: M
authors.lastname: Deenadayal
authors.forename: Nalini
authors.initials: N
authors.lastname: Gupta
authors.forename: Baidyanath
authors.initials: B
authors.lastname: Chakrabarty
authors.forename: Lalji
authors.initials: L
authors.lastname: Singh
mesh_terms: D000293:Adolescent; D000328:Adult; D055430:Bone Morphogenetic Protein 15; D016022:Case-Control Studies; D005260:Female; 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