title: BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To determine how mutations associated with ovarian dysfunction alter the biological activity of human BMP15.
  
  
  METHODS
  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.affiliation: 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.|Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Liliana C
authors.initials: LC
authors.lastname: Patiño
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.|Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Walton
authors.affiliation: Department of Plant Physiology and Biophysics, University Wuerzburg, D-97082 Wuerzburg, Germany.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Mueller
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.|Swinburne University of Technology, Hawthorn, Victoria 3122, Australia; and.
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Johnson
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.|Swinburne University of Technology, Hawthorn, Victoria 3122, Australia; and.
authors.forename: William
authors.initials: W
authors.lastname: Stocker
authors.affiliation: School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Dulama
authors.initials: D
authors.lastname: Richani
authors.affiliation: School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Agapiou
authors.affiliation: School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gilchrist
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Laissue
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.|Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Harrison
mesh_terms: D000328:Adult; D055430:Bone Morphogenetic Protein 15 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D055429:Growth Differentiation Factor 9 / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D016649:Primary Ovarian Insufficiency / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C525901:BMP15 protein, human; D055430:Bone Morphogenetic Protein 15; C525897:GDF9 protein, human; D055429:Growth Differentiation Factor 9