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Implication of Novel BMP15 and GDF9 Variants in Unexpected Poor Ovarian Response

  • Reproductive Genetics: Original Article
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Abstract

Unexpected poor ovarian response (UPOR) occurs when nine or fewer oocytes are retrieved from a young patient with normal ovarian reserve. Bone morphogenetic protein15 (BMP15) and growth differentiation factor 9 (GDF9) are two oocyte-specific factors with pivotal role in folliculogenesis. The aim of this study was to assess the relation between BMP15 and GDF9 variants with UPOR. Hundred women aged ≤ 39 with AMH ≥ 1.27 IU/ml participated as UPOR and normal ovarian responders (NOR) based on their oocyte number. Each group consisted of 50 patients. After genomic DNA extraction, the entire exonic regions of BMP15 and GDF9 were amplified and examined by direct sequencing. Western blotting was performed to determine the expression levels of BMP15 and GDF9 in follicular fluid. Additionally, in silico analysis was applied to predict the effect of discovered mutations. From four novel variants of BMP15 and GDF9 genes, silent mutations (c.744 T > C) and (c.99G > A) occurred in both groups, whereas missense variants: c.967-968insA and c.296A > G were found exclusively in UPORs. The latter variants caused reduction in protein expression. Moreover, the mutant allele (T) in a GDF9 polymorphism (C447T) found to be more in NOR individuals (58% NOR vs. 37% UPOR (OR = 2.3, CI 1.32–4.11, p = 0.004).

The novel missense mutations which were predicted as damaging, along with other mutations that happened in UPORs might result in ovarian resistance to stimulation. The mutant allele (T) in C447T polymorphism has a protective effect. It can be concluded that there is an association between BMP15 and GDF9 variants and follicular development and ovarian response.

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Data Availability

The data that support the findings of this study are available from the corresponding author on request.

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Authors and Affiliations

  1. Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Anahita Mehdizadeh, Mansoureh Soleimani, Fatemehsadat Amjadi & Zahra Zandieh

  2. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran

    Mansoureh Soleimani

  3. Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Iran University of Medical Sciences, Tehran, Iran

    Fatemehsadat Amjadi, Azadeh Akbari Sene & Zahra Zandieh

  4. Department of Medical Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Mohammad Hassan Sheikhha

  5. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Ali Dehghani

  6. Afzalipour Clinical Center for Infertility, Kerman University of Medical Sciences, Kerman, Iran

    Sareh Ashourzadeh

  7. FRANZCOG Rockingham Peel Group, South Metropolitan Health Service, Murdoch, Australia

    Bibi Shahnaz Aali

  8. Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran

    Shahriar Dabiri

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  1. Anahita Mehdizadeh
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Mehdizadeh, A., Soleimani, M., Amjadi, F. et al. Implication of Novel BMP15 and GDF9 Variants in Unexpected Poor Ovarian Response. Reprod. Sci. 31, 840–850 (2024). https://doi.org/10.1007/s43032-023-01370-1

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  • DOI: https://doi.org/10.1007/s43032-023-01370-1

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