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.

Insight into the Genomics of Premature Ovarian Failure

“…The BMP15, as one of the member of TGFβ superfamily, encodes a growth and differentiation factor, which regulates follicle maturation, follicular germ cells sensitivity to FSH action, germ cells apoptosis, oocyte developmental competence, and ovulation [41][42][43][44]. In humans, several missense variations in BMP15 gene have been found in association with POF with a frequency between 1.5 and 12% [45][46][47]. A reduced production of bioactive BMP15 protein, probably due to a mechanism of haploinsufficiency, may lead to ovarian dysgenesis through: i) an impairment of the antiapoptotic effects on germinal cells, then favoring follicle atresia; ii) an altered recruitment of pre-antral follicles by gonadotropins [33].…”

Recent advances in the study of genes involved in non-syndromic premature ovarian failure

“…In sheep, genes associated with inherited patterns of ovulation rate and prolificacy have been described, such as Inverdale (FecX I ), Booroola (FecB), Cambridge (FecC), Javanese (FecJ), Thoka (FecI) and Woodlands (FecX2) (Davis et al, 1982, 1991, 2004, Hanrahan et al, 1985, Bradford et al, 1986. Interestingly, mutations in BMP15 (GDF-9B), the human FecX orthologous gene, have been recently associated with non-syndromic POF (Di Pasquale et al, 2004, Laissue et al, 2006, Dixit et al, 2006a. Furthermore, sequence variants of GDF9, a BMP15 paralog, have shown a potential implication in non-syndromic POF pathogenesis and twinning (Laissue et.…”

“…Subsequently, in order to further assess their implication in POF pathogenesis, large panels of patients were analyzed in various populations (Di Pasquale et al, 2004, Laissue et al, 2006, Dixit et al, 2005, 2006a, Chand et al, 2006, Kovanci et al, 2007, Takebayashi et al, 2000. Surprisingly, despite the extensive number of patients screened for mutations in the coding sequences of BMP15 (n=626) and GDF9 (n=512), a small number of potentially deleterious variants have been described (Table 1 and figure 1).…”

“…Indeed, these mutations are located at conserved amino acid positions in mammalian species and are suggested to produce deleterious effects M a n u s c r i p t by in silico analyses (Di Pasquale et al, 2004, Dixit et al, 2006a, Laissue et al, 2006. Although all human BMP15 mutations are heterozygous, a homozygous mutation, c.631C>T (p.Glu211X, located in the propeptide) has been observed in an Indian patient.…”

“…Furthermore, sequence variants in Xlinked genes have been associated with POF. This is the case of BMP15, an oocyte-expressed gene Page 4 of 38 A c c e p t e d M a n u s c r i p t whose mutations have been related to mammalian ovarian dysfunction (Galloway et al, 2000, Di Pasquale et al, 2004, Laissue et al, 2006, Dixit et al, 2006a. Mutations in autosomal genes (i.e FSHR,LHR,GDF9,INHA,GALT and FOXL2) have been also linked to POF pathogenesis in syndromic and non-syndromic cases (Aittomaki et al, 1995, Latronico et al, 1996, Laissue et al, 2006, Dixit et al, 2004, 2006b, Shelling et al, 2000, Guerrero et al, 2000, Crisponi et al, 2001, Goswami et al, 2005.…”