- Email: [email protected]
BMP15, fertility and the ovary
Reproductive BioMedicine Online (2014) 29, 525–526
w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
EDITORIAL
BMP15, fertility and the ovary Premature ovarian failure (POF), also known as premature menopause, is defined as at least six months of amenorrhea before the age of 40 with elevated gonadotrophins and depressed 17-β-oestrogen (E2) levels (Dixit et al., 2010, Fonesca et al., 2014). POF affects some approximately 1% of women (Chatterjee et al., 2007). Previous studies have demonstrated a functional association between POF and polymorphisms in the promotor of bone morphogenetic protein 15 (BMP15). The BMP family is the largest group in the transforming growth factor β superfamily (Abir and Fisch, 2011; Margulis et al., 2009; Shimasaki et al., 2004). BMPs, and especially BMP15, have been shown to play a range of roles in ovarian regulation. BMP15 (growth and differentiation factor 9B) is an X-linked gene that encodes a protein that is secreted from oocytes beyond the primordial/primary stages (Abir and Fisch, 2011; Fabre et al., 2006; Hanevik et al., 2011; Margulis et al., 2009; Shimasaki et al., 2004). A correlation between deletions in the BMP15 gene and ovarian hyperstimulation syndrome (OHSS) has also been demonstrated. Thus, Moron et al. (2006) showed that a missense mutation in codon 103 disrupts the secondary structure of human OHSSBMP15-associated protein, and that the haplotype TGGA was over–represented in women with OHSS (with a higher number of heterozygous than homozygous patients). Hanevik et al. (2011) showed the involvement in low responders of another single nucleotide polymorphism (SNP): the BMP15 905G allele. Others have identified two genetic polymorphisms (−9C>G and IVS1+905A>G) that are associated with anovulation or infertility in women with polycystic ovary syndrome (PCOS) (Gonzalez et al., 2008). Moreover, in PCOS, the heterozygous genotype for IVS1+905A>G has a protective effect against anovulation and infertility. In two sisters, a heterozygous nonconservative substitution (Y235C) in the pro region of the BMP15 allele led to an activating SNP in the BMP15 gene (Fabre et al., 2006; Margulis et al., 2008; Shimasaki et al., 2004) that resulted in hypergonadotrophic ovarian failure, ovarian dysgensis and inhibition of granulosa cell proliferation. There are five naturally occurring point mutations in the BMP15 gene in sheep (Abir and Fisch, 2011; Fabre et al., 2006; Margulis et al., 2009; Shimasaki et al., 2004). Studies have shown that ewes heterozygous for these mutations usually had increased ovulation rates (without increased gonadotrophin
secretion), and occasionally had an increasing sensitivity to luteinizing hormone in antral follicles. In contrast, homozygous sheep were infertile, characterized by early folliculogenesis arrest of folliculogenesis at late primary stages, ovarian dysgenesis and failure, and streak ovaries with, occasionally, abnormal tumor-like structures, high gonadotrophin levels and undetectable E2 or inhibin levels. In ewes with other homozygous BMP15 mutations, sterility was due to ovarian hypoplasia, with occasional antral follicles containing abnormal oocytes. BMP15 has also been shown to affect early folliculogenesis in humans (Fonesca et al., 2014; Kedem et al., 2011; Margulis et al., 2009). Furthermore, in women, there was a direct correlation between an increase in BMP15 levels in follicular fluid and higher oocyte and embryonic quality (Wu et al., 2007). Indeed, in higher mammals such as sheep and humans BMP15 is almost the only gene in which deletions affect the ovary in numerous directions (Abir and Fisch, 2011; Fabre et al., 2006; Hanevik et al., 2011; Margulis et al., 2009; Moron et al., 2006; Shimasaki et al., 2004) including impaired early folliculogenesis, excessive ovulation, OHSS and POF. Several studies have reported an association between the variant BMP15 c.-9>G and POF (Hanevik et al., 2011; Moron et al., 2006). Now, in a study reported in this issue of RBM Online, Fonesca et al. (2014) have confirmed this association, and have attempted to determine whether the c.-9>G variant does indeed lead to BMP15 promoter disturbances, by using bioinformatics, real time polymerase chain reactions (on ovarian tissue from mice and humans) and Luciferase reporter assays (in assays in silico and in vitro). They report that the c.-9>G BMP15 variant results in modification of its binding sites for PITX1 transcription factor, is co-expressed with PITX1 in human and mouse tissue, and that PITX1 trans-activates both variants of the BMP15 promoter (-9C and −9G). As a result, the BMP15 c.-9>G allele was associated with increased transcription of BMP15, and with PITXI-regulated BMP15 transcription. Thus, c.-9>G is implicated in the increased occurrence of POF through the recruitment of an elevated number of follicles/oocytes early in a woman’s life. It would be worthwhile to investigate further the connection between the BMP15 c.-9>G variant and the ovaries of women with POF by in vitro and in silico techniques, to determine if these
http://dx.doi.org/10.1016/j.rbmo.2014.09.007 1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
526 nucleotide variants are responsible for defects in the PITX1 transcription factor binding site in POF, as well as to study other ovarian normal and abnormal functions related to BMP15.
References Abir, R., Fisch, B., 2011. Invited commentary: a single nucleotide polymorphism in BMP15 is associated with high response to controlled ovarian hyperstimulation. Reprod. Biomed. Online 23, 77– 80. Chatterjee, S., Modi, D., Maitra, A., Kadam, S., Patel, Z., Gokral, J., Meherji, P., 2007. Screening for FOXL2 gene mutations in women with premature ovarian failure: an Indian experience. Reprod. Biomed. Online 15, 554–560. Dixit, H., Rao, L., Padmalatha, V., Raseswarl, T., Kapu Kumar, A., Panda, B., Murthy, K., Tosh, D., Nallari, P., Deenadayal, M., Gupta, N., Chakrabarthy, B., Singh, L., 2010. Genes governing premature ovarian failure. Reprod. Biomed. Online 20, 724–740. Fabre, S., Pierre, A., Mulsant, P., Bodin, L., Elisa Di Pasquale, E., Persani, L., Monget, P., Monniaux, D., 2006. Regulation of ovulation rate in mammals: contribution of sheep genetic models. Reprod. Biol. Endocrinol. 4, 1–12. Gonzalez, A., Ramirez-Lorca, R., Calatayud, C., Mendoza, N., Ruiz, A., Saez, M.E., Moron, F.J., 2008. Association of genetic markers within the BMP15 gene with anovulation and infertility in women with polycystic ovary syndrome. Fertil. Steril. 90, 447–449. Hanevik, H.I., Hilmarsen, H.T., Skyelbred, C.F., Tanbo, T., Kahn, J.A., 2011. A single nucleotide polymorphism in BMP15 is associated with high response to controlled ovarian hypestimulation. Reprod. Biomed. Online 23, 97–104. Kedem, A., Fisch, B., Garor, R., Ben-Zaken, A., Gizunterman, T., Felz, C., Ben-Haroush, A., Kravarusic, D., Abir, R., 2011. Growth differentiating factor 9 (GDF9) and bone morphogenetic protein 15
Editorial both activate development of human primordial follicles in vitro, with seemingly more beneficial effects of GDF9. JCEM 96, 1246– 1254. Margulis, S., Abir, R., Felz, C., Nitke, S., Krissi, H., Fisch, B., 2009. Bone morphogenetic protein 15 expression in human ovaries from fetuses, girls and women. Fertil. Steril. 92, 1666–1673. Moron, F.J., de Castro, F., Royo, J.L., Montoro, L., Mira, E., Saez, M.E., Real, L.M., Gonzalez, A., Manes, S., Ruiz, A., 2006. Bone morphogenetic protein 15 (BMP15) alleles predict over-response to recombinant follicle stimulating hormone and iatrogenic ovarian hyperstimulation syndrome (OHSS). Pharmacogenet. Genomics 16, 485–495. Shimasaki, S., Moore, R.K., Otsuka, F., Erickson, G.F., 2004. The bone morphogenetic protein system in mammalian reproduction. Endocr. Rev. 25, 72–101. Wu, Y.T., Tang, L., Cai, J., Lu, X.E., Xu, J., Zhu, X.M., Luo, Q., Hunag, H.F., 2007. High bone morphogenetic protein-15 level in follicular fluid is associated with high quality oocyte and subsequent embryonic development. Hum. Reprod. 22, 1526–1531.
Ronit Abir E-mail address: [email protected]
Benjamin Fisch E-mail address: bfi[email protected]
Martin H. Johnson E-mail address: offi[email protected]
w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
EDITORIAL
BMP15, fertility and the ovary Premature ovarian failure (POF), also known as premature menopause, is defined as at least six months of amenorrhea before the age of 40 with elevated gonadotrophins and depressed 17-β-oestrogen (E2) levels (Dixit et al., 2010, Fonesca et al., 2014). POF affects some approximately 1% of women (Chatterjee et al., 2007). Previous studies have demonstrated a functional association between POF and polymorphisms in the promotor of bone morphogenetic protein 15 (BMP15). The BMP family is the largest group in the transforming growth factor β superfamily (Abir and Fisch, 2011; Margulis et al., 2009; Shimasaki et al., 2004). BMPs, and especially BMP15, have been shown to play a range of roles in ovarian regulation. BMP15 (growth and differentiation factor 9B) is an X-linked gene that encodes a protein that is secreted from oocytes beyond the primordial/primary stages (Abir and Fisch, 2011; Fabre et al., 2006; Hanevik et al., 2011; Margulis et al., 2009; Shimasaki et al., 2004). A correlation between deletions in the BMP15 gene and ovarian hyperstimulation syndrome (OHSS) has also been demonstrated. Thus, Moron et al. (2006) showed that a missense mutation in codon 103 disrupts the secondary structure of human OHSSBMP15-associated protein, and that the haplotype TGGA was over–represented in women with OHSS (with a higher number of heterozygous than homozygous patients). Hanevik et al. (2011) showed the involvement in low responders of another single nucleotide polymorphism (SNP): the BMP15 905G allele. Others have identified two genetic polymorphisms (−9C>G and IVS1+905A>G) that are associated with anovulation or infertility in women with polycystic ovary syndrome (PCOS) (Gonzalez et al., 2008). Moreover, in PCOS, the heterozygous genotype for IVS1+905A>G has a protective effect against anovulation and infertility. In two sisters, a heterozygous nonconservative substitution (Y235C) in the pro region of the BMP15 allele led to an activating SNP in the BMP15 gene (Fabre et al., 2006; Margulis et al., 2008; Shimasaki et al., 2004) that resulted in hypergonadotrophic ovarian failure, ovarian dysgensis and inhibition of granulosa cell proliferation. There are five naturally occurring point mutations in the BMP15 gene in sheep (Abir and Fisch, 2011; Fabre et al., 2006; Margulis et al., 2009; Shimasaki et al., 2004). Studies have shown that ewes heterozygous for these mutations usually had increased ovulation rates (without increased gonadotrophin
secretion), and occasionally had an increasing sensitivity to luteinizing hormone in antral follicles. In contrast, homozygous sheep were infertile, characterized by early folliculogenesis arrest of folliculogenesis at late primary stages, ovarian dysgenesis and failure, and streak ovaries with, occasionally, abnormal tumor-like structures, high gonadotrophin levels and undetectable E2 or inhibin levels. In ewes with other homozygous BMP15 mutations, sterility was due to ovarian hypoplasia, with occasional antral follicles containing abnormal oocytes. BMP15 has also been shown to affect early folliculogenesis in humans (Fonesca et al., 2014; Kedem et al., 2011; Margulis et al., 2009). Furthermore, in women, there was a direct correlation between an increase in BMP15 levels in follicular fluid and higher oocyte and embryonic quality (Wu et al., 2007). Indeed, in higher mammals such as sheep and humans BMP15 is almost the only gene in which deletions affect the ovary in numerous directions (Abir and Fisch, 2011; Fabre et al., 2006; Hanevik et al., 2011; Margulis et al., 2009; Moron et al., 2006; Shimasaki et al., 2004) including impaired early folliculogenesis, excessive ovulation, OHSS and POF. Several studies have reported an association between the variant BMP15 c.-9>G and POF (Hanevik et al., 2011; Moron et al., 2006). Now, in a study reported in this issue of RBM Online, Fonesca et al. (2014) have confirmed this association, and have attempted to determine whether the c.-9>G variant does indeed lead to BMP15 promoter disturbances, by using bioinformatics, real time polymerase chain reactions (on ovarian tissue from mice and humans) and Luciferase reporter assays (in assays in silico and in vitro). They report that the c.-9>G BMP15 variant results in modification of its binding sites for PITX1 transcription factor, is co-expressed with PITX1 in human and mouse tissue, and that PITX1 trans-activates both variants of the BMP15 promoter (-9C and −9G). As a result, the BMP15 c.-9>G allele was associated with increased transcription of BMP15, and with PITXI-regulated BMP15 transcription. Thus, c.-9>G is implicated in the increased occurrence of POF through the recruitment of an elevated number of follicles/oocytes early in a woman’s life. It would be worthwhile to investigate further the connection between the BMP15 c.-9>G variant and the ovaries of women with POF by in vitro and in silico techniques, to determine if these
http://dx.doi.org/10.1016/j.rbmo.2014.09.007 1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
526 nucleotide variants are responsible for defects in the PITX1 transcription factor binding site in POF, as well as to study other ovarian normal and abnormal functions related to BMP15.
References Abir, R., Fisch, B., 2011. Invited commentary: a single nucleotide polymorphism in BMP15 is associated with high response to controlled ovarian hyperstimulation. Reprod. Biomed. Online 23, 77– 80. Chatterjee, S., Modi, D., Maitra, A., Kadam, S., Patel, Z., Gokral, J., Meherji, P., 2007. Screening for FOXL2 gene mutations in women with premature ovarian failure: an Indian experience. Reprod. Biomed. Online 15, 554–560. Dixit, H., Rao, L., Padmalatha, V., Raseswarl, T., Kapu Kumar, A., Panda, B., Murthy, K., Tosh, D., Nallari, P., Deenadayal, M., Gupta, N., Chakrabarthy, B., Singh, L., 2010. Genes governing premature ovarian failure. Reprod. Biomed. Online 20, 724–740. Fabre, S., Pierre, A., Mulsant, P., Bodin, L., Elisa Di Pasquale, E., Persani, L., Monget, P., Monniaux, D., 2006. Regulation of ovulation rate in mammals: contribution of sheep genetic models. Reprod. Biol. Endocrinol. 4, 1–12. Gonzalez, A., Ramirez-Lorca, R., Calatayud, C., Mendoza, N., Ruiz, A., Saez, M.E., Moron, F.J., 2008. Association of genetic markers within the BMP15 gene with anovulation and infertility in women with polycystic ovary syndrome. Fertil. Steril. 90, 447–449. Hanevik, H.I., Hilmarsen, H.T., Skyelbred, C.F., Tanbo, T., Kahn, J.A., 2011. A single nucleotide polymorphism in BMP15 is associated with high response to controlled ovarian hypestimulation. Reprod. Biomed. Online 23, 97–104. Kedem, A., Fisch, B., Garor, R., Ben-Zaken, A., Gizunterman, T., Felz, C., Ben-Haroush, A., Kravarusic, D., Abir, R., 2011. Growth differentiating factor 9 (GDF9) and bone morphogenetic protein 15
Editorial both activate development of human primordial follicles in vitro, with seemingly more beneficial effects of GDF9. JCEM 96, 1246– 1254. Margulis, S., Abir, R., Felz, C., Nitke, S., Krissi, H., Fisch, B., 2009. Bone morphogenetic protein 15 expression in human ovaries from fetuses, girls and women. Fertil. Steril. 92, 1666–1673. Moron, F.J., de Castro, F., Royo, J.L., Montoro, L., Mira, E., Saez, M.E., Real, L.M., Gonzalez, A., Manes, S., Ruiz, A., 2006. Bone morphogenetic protein 15 (BMP15) alleles predict over-response to recombinant follicle stimulating hormone and iatrogenic ovarian hyperstimulation syndrome (OHSS). Pharmacogenet. Genomics 16, 485–495. Shimasaki, S., Moore, R.K., Otsuka, F., Erickson, G.F., 2004. The bone morphogenetic protein system in mammalian reproduction. Endocr. Rev. 25, 72–101. Wu, Y.T., Tang, L., Cai, J., Lu, X.E., Xu, J., Zhu, X.M., Luo, Q., Hunag, H.F., 2007. High bone morphogenetic protein-15 level in follicular fluid is associated with high quality oocyte and subsequent embryonic development. Hum. Reprod. 22, 1526–1531.
Ronit Abir E-mail address: [email protected]
Benjamin Fisch E-mail address: bfi[email protected]
Martin H. Johnson E-mail address: offi[email protected]