BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9

Liliana C Patiño, Kelly L Walton, Thomas D Mueller, Katharine E Johnson, William Stocker, Dulama Richani, David Agapiou, Robert B Gilchrist, Paul Laissue, Craig A Harrison

Resultado de la investigación: Contribución a RevistaArtículo

10 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)1009-1019
Número de páginas11
PublicaciónJournal of Clinical Endocrinology and Metabolism
Volumen102
N.º3
DOI
EstadoPublished - mar 1 2017
Publicado de forma externa

Huella dactilar

Primary Ovarian Insufficiency
Mutation
Bone Morphogenetic Protein 15
Growth Differentiation Factor 9
Proteins
Physiology
Bioactivity
Granulosa Cells
Intercellular Signaling Peptides and Proteins
Ovulation
Chemical activation
Human Activities
Oocytes
Ovary

Citar esto

Patiño, L. C., Walton, K. L., Mueller, T. D., Johnson, K. E., Stocker, W., Richani, D., ... Harrison, C. A. (2017). BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9. Journal of Clinical Endocrinology and Metabolism, 102(3), 1009-1019. https://doi.org/10.1210/jc.2016-3503
Patiño, Liliana C ; Walton, Kelly L ; Mueller, Thomas D ; Johnson, Katharine E ; Stocker, William ; Richani, Dulama ; Agapiou, David ; Gilchrist, Robert B ; Laissue, Paul ; Harrison, Craig A. / BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9. En: Journal of Clinical Endocrinology and Metabolism. 2017 ; Vol. 102, N.º 3. pp. 1009-1019.
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title = "BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9",
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.",
author = "Pati{\~n}o, {Liliana C} and Walton, {Kelly L} and Mueller, {Thomas D} and Johnson, {Katharine E} and William Stocker and Dulama Richani and David Agapiou and Gilchrist, {Robert B} and Paul Laissue and Harrison, {Craig A}",
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Patiño, LC, Walton, KL, Mueller, TD, Johnson, KE, Stocker, W, Richani, D, Agapiou, D, Gilchrist, RB, Laissue, P & Harrison, CA 2017, 'BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9', Journal of Clinical Endocrinology and Metabolism, vol. 102, n.º 3, pp. 1009-1019. https://doi.org/10.1210/jc.2016-3503

BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9. / Patiño, Liliana C; Walton, Kelly L; Mueller, Thomas D; Johnson, Katharine E; Stocker, William; Richani, Dulama; Agapiou, David; Gilchrist, Robert B; Laissue, Paul; Harrison, Craig A.

En: Journal of Clinical Endocrinology and Metabolism, Vol. 102, N.º 3, 01.03.2017, p. 1009-1019.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9

AU - Patiño, Liliana C

AU - Walton, Kelly L

AU - Mueller, Thomas D

AU - Johnson, Katharine E

AU - Stocker, William

AU - Richani, Dulama

AU - Agapiou, David

AU - Gilchrist, Robert B

AU - Laissue, Paul

AU - Harrison, Craig A

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

U2 - 10.1210/jc.2016-3503

DO - 10.1210/jc.2016-3503

M3 - Article

C2 - 28359091

VL - 102

SP - 1009

EP - 1019

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 3

ER -