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

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

doi:10.1210/jc.2016-3503

Cited by 27 publications

(21 citation statements)

References 38 publications

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“…In addition, abnormalities in Gdf9 and BMP15 expression are associated with polycystic ovarian syndrome (PCOS) and primary ovarian insufficiency (POI) in humans [48–50]. The receptor Scarb1 was differentially expressed in DDT lineage granulosa and has been associated with POI [51].…”

Section: Discussionmentioning

confidence: 99%

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

et al. 2018

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Two of the most prevalent ovarian diseases affecting women’s fertility and health are Primary Ovarian Insufficiency (POI) and Polycystic Ovarian Syndrome (PCOS). Previous studies have shown that exposure to a number of environmental toxicants can promote the epigenetic transgenerational inheritance of ovarian disease. In the current study, transgenerational changes to the transcriptome and epigenome of ovarian granulosa cells are characterized in F3 generation rats after ancestral vinclozolin or DDT exposures. In purified granulosa cells from 20-day-old F3 generation females, 164 differentially methylated regions (DMRs) (P < 1 x 10−6) were found in the F3 generation vinclozolin lineage and 293 DMRs (P < 1 x 10−6) in the DDT lineage, compared to controls. Long noncoding RNAs (lncRNAs) and small noncoding RNAs (sncRNAs) were found to be differentially expressed in both the vinclozolin and DDT lineage granulosa cells. There were 492 sncRNAs (P < 1 x 10−4) in the vinclozolin lineage and 1,085 sncRNAs (P < 1 x 10−4) in the DDT lineage. There were 123 lncRNAs and 51 lncRNAs in the vinclozolin and DDT lineages, respectively (P < 1 x 10−4). Differentially expressed mRNAs were also found in the vinclozolin lineage (174 mRNAs at P < 1 x 10−4) and the DDT lineage (212 mRNAs at P < 1 x 10−4) granulosa cells. Comparisons with known ovarian disease associated genes were made. These transgenerational epigenetic changes appear to contribute to the dysregulation of the ovary and disease susceptibility that can occur in later life. Observations suggest that ancestral exposure to toxicants is a risk factor that must be considered in the molecular etiology of ovarian disease.

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Section: Discussionmentioning

confidence: 99%

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

et al. 2018

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“…In brief, COV434 cells were plated at 75,000 cells per well in 48-well plates in complete medium (DMEM supplemented with 10% fetal calf serum) at 37°C in 5% carbon dioxide. Following overnight incubation, cells were transfected with 250 ng perwell of a BMP response element–luciferase reporter (BRE-reporter as previously described [14]) using Lipofectamine 3000 (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions. At 24 hours posttransfection, the COV434 cells were treated with increasing doses of conditioned media containing the BMP7 variants for 16 hours.…”

Section: Methodsmentioning

confidence: 99%

“…At 24 hours posttransfection, the COV434 cells were treated with increasing doses of conditioned media containing the BMP7 variants for 16 hours. The medium was then aspirated, the cells were solubilized in solubilization buffer [25 mm glycylglycine (pH 7.8), 15 mm magnesium sulfate, 4 mm EGTA, 1% Triton X-100, and 1 mm dithiothreitol], and luciferase reporter activity was measured, as previously described [14]. Data were analyzed using Graphpad Prism 7 software and expressed as fold of nontreated wells (fold-control).…”

Section: Methodsmentioning

confidence: 99%

Functional Characterization of Two New Variants in the Bone Morphogenetic Protein 7 Prodomain in Two Pairs of Monozygotic Twins With Hypospadias

Bouty

Walton

Listyasari

et al. 2019

Journal of the Endocrine Society

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Context Variants in bone morphogenetic protein 7 (BMP7) have been reported in patients with hypospadias. Here we report and analyze two variants in the BMP7 prodomain in monozygotic twins with hypospadias. Materials and Methods Patients with hypospadias were prospectively recruited. After informed consent was obtained, DNA was extracted from blood. The coding regions of 1034 genes [including 64 known diagnostic genes and candidate genes for disorder/difference of sex development (DSD)] were sequenced using a targeted capture approach (HaloPlex, Agilent, Santa Clara, CA), combined with massively parallel sequencing. The resulting variants were filtered for rarity in the general population (<1%) and in our screen. Quality, depth of the reads, and predicted pathogenicity were also considered. The consequences of the identified mutations on BMP7 expression was determined by Western blot analysis on culture media from transfected cells, and activity measured using a SMAD 1/5-responsiveness luciferase assay. Results We analyzed DNA from 46 patients with hypospadias. Two variants in BMP7 were identified in two pairs of monozygotic concordant twins exhibiting proximal hypospadias. Both variants are heterozygous, nonsynonymous, and affect highly conserved amino acids in the prodomain of BMP7 in regions predicted to be important for BMP7 assembly/folding. Functional analyses demonstrated that both variants disrupt BMP7 synthesis or secretion. Conclusion Through our targeted DSD panel we have identified two variants in the prodomain of BMP7 in hypospadias. By decreasing BMP7 synthesis, these variants are likely to limit BMP7 bioavailability during closure of the urethral plate.Further analysis of patients with hypospadias may uncover additional variants that cause this DSD.

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“…Transient transfection of HEK293 cells with GDF9 variants either alone or in combination with BMP15, followed by Western blotting of conditioned media and cell lysates was carried out as described previously [17]. (100 nM) was added 24 h after transfection.…”

Section: Western Blotmentioning

confidence: 99%

New insights into the genetic basis of premature ovarian insufficiency: Novel causative variants and candidate genes revealed by genomic sequencing

Jaillard¹,

Bell²,

Akloul³

et al. 2020

Maturitas

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

Abstract: 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.

Cited by 27 publications

References 38 publications

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

Functional Characterization of Two New Variants in the Bone Morphogenetic Protein 7 Prodomain in Two Pairs of Monozygotic Twins With Hypospadias

New insights into the genetic basis of premature ovarian insufficiency: Novel causative variants and candidate genes revealed by genomic sequencing

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