Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/120885
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Type: Journal article
Title: BMP15 mutations associated with primary ovarian insufficiency reduce expression, activity, or synergy with gdf9
Author: Patino, L.
Walton, K.
Mueller, T.
Johnson, K.
Stocker, W.
Richani, D.
Agapiou, D.
Gilchrist, R.
Laissue, P.
Harrison, C.
Citation: Journal of Clinical Endocrinology and Metabolism, 2017; 102(3):1009-1019
Publisher: Endocrine Society
Issue Date: 2017
ISSN: 0021-972X
1945-7197
Statement of
Responsibility: 
Liliana C. Patino, Kelly L. Walton, Thomas D. Mueller, Katharine E. Johnson, William Stocker, Dulama Richani ... Robert B. Gilchrist
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.
Keywords: Bone Morphogenetic Protein 15
Rights: © 2017 by the Endocrine Society
DOI: 10.1210/jc.2016-3503
Grant ID: http://purl.org/au-research/grants/nhmrc/1078879
http://purl.org/au-research/grants/nhmrc/1062762
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