title: BMP15 c.-9C>G promoter sequence variant may contribute to the cause of non-syndromic premature ovarian failure.
abstract: 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.
authors.affiliation: Unidad de Genética, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia; Departamento de Fertilidad Humana, Genética Molecular de Colombia, Bogotá, Colombia.
authors.forename: Dora Janeth
authors.initials: DJ
authors.lastname: Fonseca
authors.affiliation: Unidad de Genética, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia.
authors.forename: Oscar
authors.initials: O
authors.lastname: Ortega-Recalde
authors.affiliation: Department of Reproductive Genetics, Fertility and Sterility Colombian Center, Bogotá, Colombia.
authors.forename: Clara
authors.initials: C
authors.lastname: Esteban-Perez
authors.affiliation: Department of Reproductive Genetics, Fertility and Sterility Colombian Center, Bogotá, Colombia.
authors.forename: Harold
authors.initials: H
authors.lastname: Moreno-Ortiz
authors.affiliation: Unidad de Genética, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia.
authors.forename: Liliana Catherine
authors.initials: LC
authors.lastname: Patiño
authors.affiliation: Unidad de Genética, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia.
authors.forename: Olga María
authors.initials: OM
authors.lastname: Bermúdez
authors.affiliation: Unidad de Genética, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia.
authors.forename: Angela María
authors.initials: AM
authors.lastname: Ortiz
authors.affiliation: Unidad de Genética, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia; Departamento de Fertilidad Humana, Genética Molecular de Colombia, Bogotá, Colombia.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Restrepo
authors.affiliation: Unidad de Genética, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia.
authors.forename: Elkin
authors.initials: E
authors.lastname: Lucena
authors.affiliation: Unidad de Genética, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia; Departamento de Fertilidad Humana, Genética Molecular de Colombia, Bogotá, Colombia. Electronic address: paul.laissue@urosario.edu.co.
authors.forename: Paul
authors.initials: P
authors.lastname: Laissue
mesh_terms: D000483:Alleles; D000818:Animals; D001665:Binding Sites; D055430:Bone Morphogenetic Protein 15 / Q000235:genetics*; D019556:COS Cells; D002522:Chlorocebus aethiops; D019295:Computational Biology; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010053:Ovary / Q000378:metabolism*; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C525901:BMP15 protein, human; D055430:Bone Morphogenetic Protein 15; D051761:Paired Box Transcription Factors; C101485:homeobox protein PITX1; D008156:Luciferases
keywords: BMP15; PITX1; bioinformatics; female infertility; premature ovarian failure