Fundamental role of BMP15 in human ovarian folliculogenesis revealed by null and missense mutations associated with primary ovarian insufficiency
| Autor: | Palma Finelli, Silvia Moleri, Luca Persani, Ilaria Bestetti, Ilaria Ferrari, Raffaella Rossetti, Francesco Brancati, Luisa Petrone |
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| Rok vydání: | 2020 |
| Předmět: |
endocrine system
Adolescent Genotype DNA Mutational Analysis Mutation Missense SMAD Primary Ovarian Insufficiency Biology Cell Line Consanguinity 03 medical and health sciences Ovarian Follicle Western blot BMP15 Genetics medicine Humans Missense mutation Genetic Predisposition to Disease Ovarian reserve ovarian folliculogenesis Alleles Genetic Association Studies Genetics (clinical) Sequence Deletion 030304 developmental biology ovarian dysgenesis Comparative Genomic Hybridization 0303 health sciences Bone morphogenetic protein 15 medicine.diagnostic_test Homozygote 030305 genetics & heredity Colocalization GDF9 Pedigree Phenotype cumulin Cancer research Female Folliculogenesis Bone Morphogenetic Protein 15 Haploinsufficiency primary ovarian insufficiency |
| Zdroj: | Human Mutation. 41:983-997 |
| ISSN: | 1098-1004 1059-7794 |
| DOI: | 10.1002/humu.23988 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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