BMP15 mutations associated with primary ovarian insufficiency reduce expression, activity, or synergy with gdf9

Context: Bone morphogenetic protein (BMP)15 is an oocyte-specific growth factor, which, together with growth differentiation factor (GDF) 9, regulates folliculogenesis and ovulation rate. Multiple mutations in BMP15 have been identified in women with primary ovarian insufficiency (POI), supporting a pathogenic role; however, the underlying biological mechanism of many of these mutants remains unresolved. Objectives: To determine how mutations associated with ovarian dysfunction alter the biological activity of human BMP15. Design: The effects of 10 mutations in BMP15 on protein production, activation of granulosa cells, and synergy with GDF9 were assessed. Results: Sequencing of 35 patients with POI identified both an unrecognized BMP15 variant (c.986G.A, R329H) and a variant (c.581T.C, F194S) previously associated with the condition. Assessing expression and activity of these and 8 other BMP15 mutants identified: (1) multiple variants, including L148P, F194S, and Y235C, with reduced mature protein production; (2) three variants (R138H, A180T, and R329H) with ;fourfold lower activity than wild-type BMP15; and (3) 3 variants (R68W, F194S, and N196K) with a significantly reduced ability to synergize with GDF9. Conclusions: Mutations in BMP15 associated with POI reduce mature protein production, activity, or synergy with GDF9. The latter effect is perhaps most interesting given that interactions with GDF9 most likelyunderlie the physiologyofBMP15in thehumanovary. Copyright © 2017 by the Endocrine Society.

• Fecha de publicación: 2017
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/22298
• Acceso en línea: https://doi.org/10.1210/jc.2016-3503; https://repository.urosario.edu.co/handle/10336/22298
• Palabra clave: Bone morphogenetic protein 15; Cysteine; Growth differentiation factor 9; Guanine; Histone; Tyrosine; Bone morphogenetic protein 15; Growth differentiation factor 9; Adult; Amino acid substitution; Article; Bmp15 gene; Cell activation; Controlled study; Down regulation; Female; Gene expression regulation; Gene function; Gene mutation; Gene sequence; Genetic association; Genetic variability; Granulosa cell; Human; Major clinical study; Mutational analysis; Premature ovarian failure; Protein function; Protein secondary structure; Protein secretion; Protein synthesis; Wild type; Drug effect; Gene expression; Genetics; Metabolism; Molecular model; Mutation; Premature ovarian failure; Reverse transcription polymerase chain reaction; Tumor cell line; Adult; Bone morphogenetic protein 15; Female; Gene expression; Granulosa cells; Growth differentiation factor 9; Humans; Mutation; Primary ovarian insufficiency; Reverse transcriptase polymerase chain reaction; molecular; human; human; tumor; Bmp15 protein; Gdf9 protein; Cell line; Models
• License: Abierto (Texto Completo)