Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases

Tšuiko, Olga; Nõukas, Margit; Žilina, Olga; Hensen, Kati; Tapanainen, Juha S.; Mägi, Reedik; Kals, Mart; Kivistik, Paula Ann; Haller-Kikkatalo, Kadri; Salumets, Andres; Kurg, Ants

doi:10.1093/humrep/dew142

Cited by 51 publications

(46 citation statements)

References 72 publications

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“…Herein, POI-7 has a microduplication (11.4-kb) in this gene ( Table 2 ). Furthermore, an 83.8-kb deletion in the CPBE1 gene was found in POI-14 ( Table 2 ), the same region previously identified in some POI cohorts [ 12 , 14 , 15 ]. In addition, the rare and deleterious heterozygous missense variant in CPEB1 (c.259C>T;p.Arg87Cys) was also identified in POI-4 ( Table 2 ).…”

Section: Discussionsupporting

confidence: 65%

Screening of targeted panel genes in Brazilian patients with primary ovarian insufficiency

et al. 2020

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Primary ovarian insufficiency (POI) is a heterogeneous disorder associated with several genes. The majority of cases are still unsolved. Our aim was to identify the molecular diagnosis of a Brazilian cohort with POI. Genetic analysis was performed using a customized panel of targeted massively parallel sequencing (TMPS) and the candidate variants were confirmed by Sanger sequencing. Additional copy number variation (CNV) analysis of TMPS samples was performed by CONTRA. Fifty women with POI (29 primary amenorrhea and 21 secondary amenorrhea) of unknown molecular diagnosis were included in this study, which was conducted in a tertiary referral center of clinical endocrinology. A genetic defect was obtained in 70% women with POI using the customized TMPS panel. Twenty-four pathogenic variants and two CNVs were found in 48% of POI women. Of these variants, 16 genes were identified as BMP8B , CPEB1 , INSL3 , MCM9 , GDF9 , UBR2 , ATM , STAG3 , BMP15 , BMPR2 , DAZL , PRDM1 , FSHR , EIF4ENIF1 , NOBOX , and GATA4 . Moreover, a microdeletion and microduplication in the CPEB1 and SYCE1 genes, respectively, were also identified in two distinct patients. The genetic analysis of eleven patients was classified as variants of uncertain clinical significance whereas this group of patients harbored at least two variants in different genes. Thirteen patients had benign or no rare variants, and therefore the genetic etiology remained unclear. In conclusion, next-generation sequencing (NGS) is a highly effective approach to identify the genetic diagnoses of heterogenous disorders, such as POI. A molecular etiology allowed us to improve the disease knowledge, guide decisions about prevention or treatment, and allow familial counseling avoiding future comorbidities.

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Section: Discussionsupporting

confidence: 65%

Screening of targeted panel genes in Brazilian patients with primary ovarian insufficiency

et al. 2020

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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]. The growth factor IGF1 and the receptors Pdgfra and Ghr were also differentially expressed in the DDT lineage and have been implicated in PCOS [52–54].…”

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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“…Emerging evidence in mice has identified the ontogeny of the expression patterns of this protein, which suggests it has a role in the primordial to primary transitioncontributing to transcription status of the follicle (Schultz et al 2018). However, studies in human POI cohorts reveal conflicting data, with overexpression observed in some cases, and other studies contend that TBPs do not contribute to POI (Tsuiko et al 2016. A new potential marker of primordial follicles about to undergo activation is the expression status of keratin.…”

Section: Current Research Into Primordial Follicle Activationmentioning

confidence: 99%

Advances in human primordial follicle activation and premature ovarian insufficiency

et al. 2020

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In women, the non-growing population of follicles that comprise the ovarian reserve is determined at birth and serves as the reservoir for future fertility. This reserve of dormant, primordial follicles and the mechanisms controlling their selective activation which constitute the committing step into folliculogenesis are essential for determining fertility outcomes in women. Much of the available data on the mechanisms responsible for primordial follicle activation focuses on a selection of key molecular pathways, studied primarily in animal models, with findings often not synonymous in humans. The excessive induction of primordial follicle activation may cause the development of premature ovarian insufficiency (POI), a condition characterised by menopause before age 40 years. POI affects 1–2% of all women and is accompanied by additional health risks. Therefore, it is critical to further our understanding of primordial follicle activation in order to diagnose, treat and prevent premature infertility. Research in primordial follicle activation has focused on connecting new molecules to already established key signalling pathways, such as phosphatidylinositol 3-Kinase (PI3K) and mammalian target of rapamycin (mTOR). Additionally, other aspects of the ovarian environment, such as the function of the extracellular matrix, in contributing to primordial follicle activation have gained traction. Clinical applications are examining replication of this extracellular environment through the construction of biological matrices mimicking the 3D ovary, to support follicular growth through to ovulation. This review outlines the importance of the events leading to the establishment of the ovarian reserve and highlights the fundamental factors known to influence primordial follicle activation in humans presenting new horizons for female infertility treatment.

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Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases

Cited by 51 publications

References 72 publications

Screening of targeted panel genes in Brazilian patients with primary ovarian insufficiency

Screening of targeted panel genes in Brazilian patients with 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

Advances in human primordial follicle activation and premature ovarian insufficiency

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