BMP15 c.-9C>G promoter sequence variant may contribute to the cause of non-syndromic premature ovarian failure
AuthorFonseca, Dora Janeth
Patiño, Liliana Catherine
Bermúdez, Olga María
Ortiz, Angela María
Restrepo, Carlos M.
"BMP15 has drawn particular attention in the pathophysiology of reproduction, as its mutations in mammalian species have been related to different reproductive phenotypes. In humans, BMP15 coding regions have been sequenced in large panels of women with premature ovarian failure (POF), but only some mutations have been definitely validated as causing the phenotype. A functional association between the BMP15 c.-9C>G promoter polymorphism and cause of POF have been reported. The aim of this study was to determine the potential functional effect of this sequence variant on specific BMP15 promoter transactivation disturbances. Bioinformatics was used to identify transcription factor binding sites located on the promoter region of BMP15. Reverse transcription polymerase chain reaction was used to study specific gene expression in ovarian tissue. Luciferase reporter assays were used to establish transactivation disturbances caused by the BMP15 c.-9C>G variant. The c.-9C>G variant was found to modify the PITX1 transcription factor binding site. PITX1 and BMP15 co-expressed in human and mouse ovarian tissue, and PITX1 transactivated both BMP15 promoter versions (-9C and -9G). It was found that the BMP15 c.-9G allele was related to BMP15 increased transcription, supporting c.-9C>G as a causal agent of POF. © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved."
Bone morphogenetic protein 15 ; Transcription factor ; Transcription factor pitx1 ; Unclassified drug ; Bmp15 protein, human ; Bone morphogenetic protein 15 ; Homeobox protein pitx1 ; Luciferase ; Paired box transcription factor ; Adult ; Allele ; Animal tissue ; Article ; Binding site ; Bioinformatics ; Computer model ; Controlled study ; Female ; Gene expression profiling ; Genetic association ; Human ; Human cell ; In vitro study ; Luciferase assay ; Mouse ; Nonhuman ; Nucleotide sequence ; Pathogenesis ; Premature ovarian failure ; Promoter region ; Protein binding ; Reverse transcription polymerase chain reaction ; Single nucleotide polymorphism ; Transactivation ; Animal ; Biology ; Chlorocebus aethiops ; Cos 1 cell line ; Genetic transcription ; Genetic variability ; Genetics ; Metabolism ; Mutation ; Ovary ; Phenotype ; Premature ovarian failure ; Transcription initiation ; Alleles ; Animals ; Binding sites ; Bone morphogenetic protein 15 ; Cercopithecus aethiops ; Computational biology ; Cos cells ; Female ; Genetic variation ; Humans ; Luciferases ; Mice ; Mutation ; Ovary ; Paired box transcription factors ; Phenotype ; Polymorphism, single nucleotide ; Primary ovarian insufficiency ; Promoter regions, genetic ; Transcription, genetic ; Transcriptional activation ; Bioinformatics ; Bmp15 ; Female infertility ; Pitx1 ; Premature ovarian failure ;
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