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Missense mutations in the BMP15 gene are associated with ovarian failure

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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.

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Acknowledgments

We acknowledge Ms DV Jayanthi of the Infertility Institute and Research Centre (IIRC), Secunderabad, for her help in patient recruitment. We are thankful to Dr Sujatha for her help in recruitment of the control females. We are also thankful to Dr T Ramakrishna Murti for his suggestions and for critically going through the manuscript. The study was supported by a grant from the Indian Council of Medical Research, New Delhi. H.D. was supported by fellowship from the Council of Scientific and Industrial Research (CSIR), Government of India.

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Authors and Affiliations

  1. Centre for Cellular and Molecular Biology, Uppal Road, 500007, Hyderabad, A.P, India

    Hridesh Dixit, Lakshmi K Rao, Venkata V Padmalatha, Murthy Kanakavalli & Lalji Singh

  2. Infertility Institute and Research Centre, Hyderabad, India

    Mamata Deenadayal

  3. Institute of Reproductive Medicine, Kolkata, India

    Nalini Gupta & Baidyanath Chakrabarty

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  1. Hridesh Dixit
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  2. Lakshmi K Rao
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  3. Venkata V Padmalatha
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  4. Murthy Kanakavalli
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  5. Mamata Deenadayal
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  6. Nalini Gupta
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  7. Baidyanath Chakrabarty
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  8. Lalji Singh
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Correspondence to Lalji Singh.

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Dixit, H., Rao, L.K., Padmalatha, V.V. et al. Missense mutations in the BMP15 gene are associated with ovarian failure. Hum Genet 119, 408–415 (2006). https://doi.org/10.1007/s00439-006-0150-0

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  • DOI: https://doi.org/10.1007/s00439-006-0150-0

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