Journal Article

Identification of a mutation in <i>GDF9</i> as a novel cause of diminished ovarian reserve in young women

Ting-Ting Wang, Zhang-Hong Ke, Yang Song, Lu-Ting Chen, Xi-Jing Chen, Chun Feng, Dan Zhang, Run-Ju Zhang, Yan-Ting Wu, Yu Zhang, Jian-Zhong Sheng and He-Feng Huang

in Human Reproduction

Published on behalf of European Society of Human Reproduction and Embryology

Volume 28, issue 9, pages 2473-2481
Published in print September 2013 | ISSN: 0268-1161
Published online July 2013 | e-ISSN: 1460-2350 | DOI: http://dx.doi.org/10.1093/humrep/det291
Identification of a mutation in GDF9 as a novel cause of diminished ovarian reserve in young women

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STUDY QUESTION

Do any mutations in growth differentiation factor 9 (GDF9) have a role in diminished ovarian reserve (DOR) in young women?

SUMMARY ANSWER

The GDF9 p.R146C mutation may be a source of DOR in some young women.

WHAT IS KNOWN ALREADY

DOR affects 10% of women under 37 years of age and is associated with accelerated expenditure of follicles. GDF9 is an oocyte-secreted factor that plays a critical role in follicular development and female fertility. Several GDF9 variants have been linked to ovarian dysfunction.

STUDY DESIGN, SIZE, DURATION

This case–control study included 139 women with DOR and 152 controls aged under 37 years.

PARTICIPANTS/MATERIALS, SETTING, METHODS

All women were recruited in a Chinese tertiary center and underwent DNA sequencing of GDF9 gene. We then determined the molecular and biological properties of mutant GDF9 proteins using protein expression, structural prediction and functional analyses.

MAIN RESULTS AND THE ROLE OF CHANCE

We identified two mutations in the proregion of GDF9 gene: c.169T > G (p.D57Y) and c.436T > C (p.R146C). The p.R146C mutation was found in three women with DOR but was absent in the control population. This mutation was also associated with significant reductions in GDF9 mature protein secretion in cultured cells. Functional studies with human granulosa cells (GCs) showed that the p.R146C mutation reduced the abilities of GDF9 to stimulate GC proliferation and to activate the Smad2 pathway. Protein structure modeling predicted that p.R146C disrupted an α-helix in GDF9 protein. In contrast with p.R146C, the p.D57Y mutation, found in both the DOR and control groups (6 versus 2), had no obvious deleterious effects.

LIMITATIONS, REASONS FOR CAUTION

Larger studies in varying populations may validate the role of GDF9 mutation in young women with DOR.

WIDER IMPLICATIONS OF THE FINDINGS

These results may provide new insights into the pathophysiological mechanisms of early-onset DOR.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by the National Natural Science Foundation of China (30900517 and 81100468), the National Basic Research Program of China (2012CB944901 and 2011CB944502), the Fundamental Research Funds for the Central Universities, Ministry of Education, China (2011KYJD008), Program for Changjiang Scholars and Innovative Research Team in University (IRT1184) and Program for Key Subjects Group of Reproductive Medicine at Zhejiang Province (XKQ-009-002). The authors have no competing interests to declare.

Keywords: GDF9; diminished ovarian reserve; mutation; folliculogenesis; reproductive aging

Journal Article.  4240 words.  Illustrated.

Subjects: Reproductive Medicine

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