Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure

Abstract

Background and objective: Mutations in bone morphogenic protein 15 (BMP15) and growth/differentiation factor 9 (GDF9) lead to altered fertility in animal models. In the human, a heterozygous point mutation of BMP15 has been associated with premature ovarian failure (POF). Subject and methods: We have directly sequenced both genes in a cohort of 203 POF patients presenting with primary or secondary amenorrhea and high FSH levels and in a control population including 54 women with regular menstrual cycles who had at least one child. Results: We have identified several heterozygous variants. One alteration in GDF9 (S186Y) and one in BMP15 (L148P) may have pathogenic effects as both positions are conserved in vertebrate species, ranging from the chicken to mammals. These variants were absent in the control samples. We also found synonymous and neutral substitutions. Conclusions: We propose that although mutations in BMP15 and GDF9 are not a major cause of ovarian insufficiency, they may be involved in POF.

Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure

“…Among these, GDF9 and BMP15 and more recently meiosis genes have become candidate genes for POF (13)(14)(15)27). However, they demonstrate variable clinical expressions, and their clinical relevance is not clear.…”

“…In non-syndromic forms, rare mutations in the FSH have been described, (1,(7)(8)(9), and our group has previously identified homozygous or compound heterozygous mutations of the FSHR gene in three POF patients (10)(11)(12). Some variants of other genes, such as BMP15, GDF9, and NOBOX and more recently some mutations of NR5A1 have also been reported (13)(14)(15)(16)(17)(18). Nevertheless, mutations affecting all of these genes account for a small minority of all cases of ovarian dysfunction, which suggest that there are additional factors that remain to be identified.…”

Effects of active immunization against growth differentiation factor 9 and/or bone morphogenetic protein 15 on ovarian function in cattle

“…However, the role of either of these growth factors in regulating ovulation rate in mice is equivocal. Recently, naturally occurring mutations in either GDF9 or BMP15 in humans have been linked to infertility, including primary amenorrhea (Di Pasquale et al 2004, Dixit et al 2005, Laissue et al 2006, Kovanci et al 2007, and for GDF9, to increased dizygotic twinning (Palmer et al 2006). Thus, one or both of these growth factors likely play a critical role in ovarian follicular development in mammals, although the absolute requirement and specific roles of the growth factors vary between species, potentially related to the ovulation rate quota of a particular species (Moore et al 2004).…”

Characterization of recombinant human growth differentiation factor-9 signaling in ovarian granulosa cells

“…Mutations in the hGDF9 gene are associated with various reproductive abnormalities. It has been shown that aberrant expression of GDF9 is associated with polycystic ovary syndrome (PCOS) (Teixeira Filho et al 2002) and screening of women with premature ovarian failure (POF) has revealed mutations in the GDF9 gene (Dixit et al 2005;Laissue et al 2006). In 2004 a rare deletion mutation in the hGDF9 gene was described in heterozygous sisters with spontaneous dizygotic twins (Montgomery et al 2004) and more recently new variants in the hGDF9 gene that are significantly more common in mothers of dizygotic (DZ) twins than controls were described, suggesting that rare GDF9 variants contribute to the likelihood of DZ twinning (Palmer et al 2006).…”