BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein
- 4 March 2009
- journal article
- research article
- Published by Hindawi Limited in Human Mutation
- Vol. 30 (5), 804-810
- https://doi.org/10.1002/humu.20961
Abstract
Bone morphogenetic protein‐15 (BMP15) is selectively synthesized by oocytes as a pre‐proprotein and is considered an ovarian follicle organizer whose adequate function is critical for female fertility. Missense mutations were reported in primary ovarian insufficiency (POI) but their biological impact remained unexplored. Here, screening of 300 unrelated idiopathic overt POI women with primary or secondary amenorrhea (SA) led to the identification of six heterozygous BMP15 variations in 29 of them. All alterations are nonconservative and include one insertion of three nucleotides (p.L262_L263insL) and five missense substitutions. Except for the p.S5R located in the signal sequence, the other variants (p.R68W, p.R138H, p.L148P, and p.A180T) localize in the proregion, which is essential for the processing and secretion of bioactive dimers. The mutations p.R68W, p.L148P, and the novel p.R138H lead to marked reductions of mature protein production. Their biological effects, evaluated by a novel luciferase‐reporter assay in a human granulosa cell (GC) line, were significantly reduced. Cotransfection experiments of defective mutants with equal amounts of wild‐type BMP15 cDNA, thus reproducing the heterozygous state seen in patients, did not generate a complete recovery of wild‐type activity. No or minor deleterious effects were detected for the variants p.L262_L263insL, p.A180T, or p.S5R. In conclusion, heterozygous BMP15 mutations associated with the early onset of overt POI lead to defective secretion of bioactive dimers. These findings support the concept that an adequate amount of BMP15 secreted in the follicular fluid is critical for female fertility. We propose to consider the screening of BMP15 mutations among the analyses for the prediction of POI risk. Hum Mutat 0, 1–7, 2009.This publication has 41 references indexed in Scilit:
- Variation in bone morphogenetic protein 15 is not associated with spontaneous human dizygotic twinningHuman Reproduction, 2008
- Regulation of ovulation rate in mammals: contribution of sheep genetic modelsReproductive Biology and Endocrinology, 2006
- Oocytes prevent cumulus cell apoptosis by maintaining a morphogenic paracrine gradient of bone morphogenetic proteinsJournal of Cell Science, 2005
- A clinical and molecular study of 26 females with Xp deletions with special emphasis on inherited deletionsHuman Genetics, 2005
- An update: spontaneous premature ovarian failure is not an early menopauseFertility and Sterility, 2005
- Premature ovarian failureHuman Reproduction Update, 2005
- Molecular biology and physiological role of the oocyte factor, BMP-15Molecular and Cellular Endocrinology, 2005
- Posttranslational processing of mouse and human BMP-15: Potential implication in the determination of ovulation quotaProceedings of the National Academy of Sciences of the United States of America, 2005
- The role of proteins of the transforming growth factor-β superfamily in the intraovarian regulation of follicular developmentHuman Reproduction Update, 2005
- Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1American Journal of Human Genetics, 1998