Liliana C Patiño1,2, Kelly L Walton2,3, Thomas D Mueller4, Katharine E Johnson2,5, William Stocker2,5, Dulama Richani6, David Agapiou6, Robert B Gilchrist6, Paul Laissue1, Craig A Harrison2,3. 1. Centro de Investigación en Genética y Genómica, Grupo de Investigación en Genética en Investigación de la Universidad del Rosario, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, 110010 Bogotá, Colombia. 2. Department of Physiology, Monash University, Clayton, Victoria 3800, Australia. 3. Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia. 4. Department of Plant Physiology and Biophysics, University Wuerzburg, D-97082 Wuerzburg, Germany. 5. Swinburne University of Technology, Hawthorn, Victoria 3122, Australia; and. 6. School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales 2052, Australia.
Abstract
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 likely underlie the physiology of BMP15 in the human ovary.
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 likely underlie the physiology of BMP15 in the human ovary.
Authors: William A Stocker; Kelly L Walton; Dulama Richani; Karen L Chan; Kiri H Beilby; Bethany J Finger; Mark P Green; Robert B Gilchrist; Craig A Harrison Journal: J Biol Chem Date: 2020-04-29 Impact factor: 5.157
Authors: Aurore Bouty; Kelly Walton; Nurin Aisyiyah Listyasari; Gorjana Robevska; Jocelyn Van den Bergen; Ardy Santosa; Sultana M H Faradz; Craig Harrison; Katie L Ayers; Andrew H Sinclair Journal: J Endocr Soc Date: 2019-02-22
Authors: Eric Nilsson; Rachel Klukovich; Ingrid Sadler-Riggleman; Daniel Beck; Yeming Xie; Wei Yan; Michael K Skinner Journal: Epigenetics Date: 2018-10-02 Impact factor: 4.528