Fundamental role of BMP15 in human ovarian folliculogenesis revealed by null and missense mutations associated with primary ovarian insufficiency.
Adolescent
Alleles
Bone Morphogenetic Protein 15
/ genetics
Cell Line
Comparative Genomic Hybridization
Consanguinity
DNA Mutational Analysis
Female
Genetic Association Studies
/ methods
Genetic Predisposition to Disease
Genotype
Homozygote
Humans
Mutation, Missense
Ovarian Follicle
/ growth & development
Pedigree
Phenotype
Primary Ovarian Insufficiency
/ diagnosis
Sequence Deletion
BMP15
GDF9
cumulin
ovarian dysgenesis
ovarian folliculogenesis
primary ovarian insufficiency
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
10
04
2019
revised:
09
01
2020
accepted:
16
01
2020
pubmed:
21
1
2020
medline:
22
7
2021
entrez:
21
1
2020
Statut:
ppublish
Résumé
Bone morphogenetic protein 15 (BMP15) encodes an oocyte factor with a relevant role for folliculogenesis as homodimer or cumulin heterodimer (BMP15-GDF9). Heterozygous BMP15 variants in the precursor or mature peptide had been associated with primary ovarian insufficiency (POI), but the underlying mechanism remains elusive and a double dose of BMP15 was suggested to be required for adequate ovarian reserve. We uncovered two homozygous BMP15 null variants found in two girls with POI and primary amenorrhea. Both heterozygous mothers reported physiological menopause. We then performed western blot, immunofluorescence, and reporter assays to investigate how previously reported missense variants, p.Y235C and p.R329C, located in the precursor or mature domains of BMP15, may affect protein function. The p.R329C variant demonstrates an impaired colocalization with growth/differentiation factor 9 (GDF9) at confocal images and diminished activation of the SMAD pathways at western blot and reporter assays in COV434 follicular cell line. In conclusion, BMP15 null mutations cause POI only in the homozygous state, thus discarding the possibility that isolated BMP15 haploinsufficiency can cause evident ovarian defects. Alternatively, heterozygous BMP15 missense variants may affect ovarian function by interfering with cumulin activity. Our data definitely support the fundamental role of BMP15 in human ovarian folliculogenesis.
Substances chimiques
BMP15 protein, human
0
Bone Morphogenetic Protein 15
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
983-997Informations de copyright
© 2020 Wiley Periodicals, Inc.
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