1. BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency.
- Author
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Renault L, Patiño LC, Magnin F, Delemer B, Young J, Laissue P, Binart N, and Beau I
- Subjects
- Adult, Animals, Bone Morphogenetic Protein Receptors, Type I metabolism, Female, Follow-Up Studies, Humans, Mice, NIH 3T3 Cells, Primary Ovarian Insufficiency metabolism, Primary Ovarian Insufficiency pathology, Prognosis, Signal Transduction, Biomarkers analysis, Bone Morphogenetic Protein Receptors, Type I genetics, Genetic Predisposition to Disease, Mutation, Missense, Primary Ovarian Insufficiency etiology
- Abstract
Context: Primary ovarian insufficiency (POI) is a frequently occurring disorder affecting approximately 1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone, leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene mutations, most cases remain idiopathic., Objective: To identify and to functionally validate new sequence variants in 2 genes that play a key role in mammalian ovarian function, BMPR1A and BMPR1B (encoding for bone morphogenic protein receptor), leading to POI., Methods: The impact on bone morphogenic protein (BMP) signaling of BMPR1A and BMPR1B variants, previously identified by whole-exome sequencing on 69 women affected by isolated POI, was established by different in vitro functional experiments., Results: We demonstrate that the BMPR1A-p.Arg442His and BMPR1B-p.Phe272Leu variants are correctly expressed and located but lead to an impairment of downstream BMP signaling., Conclusion: In accordance with infertility observed in mice lacking Bmpr1a in the ovaries and in Bmpr1b-/- mice, our results unveil, for the first time, a link between BMPR1A and BMPR1B variants and the origin of POI. We show that BMP signaling impairment through specific BMPR1A and BMPR1B variants is a novel pathophysiological mechanism involved in human POI. We consider that BMPR1A and BMPR1B variants constitute genetic biomarkers of the origin of POI and have clinical utility., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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