A STAG3 missense mutation in two sisters with primary ovarian insufficiency

Colombo, Roberto; Pontoglio, Alessandro; Bini, Maurizio

doi:10.1016/j.ejogrb.2017.08.005

Cited by 24 publications

(25 citation statements)

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“…The ARM-type domain is located after the STAG domain, which is predicted to interact with nucleic acid or another protein (Caburet et al, 2014) ( Figure 1E ). At present, six STAG3 variants have been reported in five families with POI (Caburet et al, 2014; Stabej et al, 2016; Colombo et al, 2017; He et al, 2018a; Franca et al, 2019) ( Table 1 ). All six variants are truncated variants that severely disrupt the STAG domain and/or ARM-type domain.…”

Section: Discussionmentioning

confidence: 99%

“…Stromal antigen 3 ( STAG3 ) is a meiosis-specific gene that is restrictedly expressed in testes and ovaries in humans, and it plays an important role in gametogenesis and fertility (Houmard et al, 2009; Nogues et al, 2009; Garciacruz et al, 2010; Caburet et al, 2014). Variants of STAG3 are rare, and only six truncated variants, three frameshift variants, two nonsense variants, and one splicing variant (Caburet et al, 2014; Stabej et al, 2016; Colombo et al, 2017; He et al, 2018a; Franca et al, 2019) ( Table 1 ) associated with POI have been reported to date. However, it remains enigmatic whether in-frame variants of STAG3 can cause POI and female infertility.…”

Section: Introductionmentioning

confidence: 99%

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In-Frame Variants in STAG3 Gene Cause Premature Ovarian Insufficiency

Xiao

Zhang

et al. 2019

Front. Genet.

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Premature ovarian insufficiency (POI) is a severe clinical syndrome defined by ovarian dysfunction in women less than 40 years old who generally manifest with infertility, menstrual disturbance, elevated gonadotrophins, and low estradiol levels. STAG3 is considered a genetic aetiology of POI, which facilitates entry of REC8 into the nucleus of a cell and plays an essential role in gametogenesis. At present, only six truncated variants associated with POI have been reported; there have been no reports of an in-frame variant of STAG3 causing POI. In this study, two novel homozygous in-frame variants (c.877_885del, p.293_295del; c.891_893dupTGA, p.297_298insAsp) in STAG3 were identified in two sisters with POI from a five-generation consanguineous Han Chinese family. To evaluate the effects of these two variants, we performed fluorescence localization and co-immunoprecipitation analyses using in vitro cell model. The two variants were shown to be pathogenic, as neither STAG3 nor REC8 entered nuclei, and interactions between mutant STAG3 and REC8 or SMC1A were absent. To the best of our knowledge, this is the first report on in-frame variants of STAG3 that cause POI. This finding extends the spectrum of variants in STAG3 and sheds new light on the genetic origins of POI.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In-Frame Variants in STAG3 Gene Cause Premature Ovarian Insufficiency

Xiao

Zhang

et al. 2019

Front. Genet.

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“…Genetic etiologies account for approximately 20–25% of POI patients, but recent advances emphasize genetic heterogeneity (Jiao et al 2015). POI causative genes isolated in POI pedigrees are mainly enriched in DNA damage repair, homologous recombination and meiosis (Jiao et al 2018), including CSB - PGBD3 (Qin et al 2015), MCM8 (Bouali et al 2017; Tenenbaum-Rakover et al 2015), MCM9 (Fauchereau et al 2016; Wood-Trageser Michelle et al 2014), MSH4 (Carlosama et al 2017), MSH5 (Guo et al 2017) and STAG3 (Caburet et al 2014; Colombo et al 2017; Le Quesne et al 2016). Nevertheless, the genetic architecture underlying sporadic POI remains complicated since either gene variants or inheritance patterns are quite different among individuals.…”

Section: Introductionmentioning

confidence: 99%

Rare variants in FANCA induce premature ovarian insufficiency

et al. 2019

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Premature ovarian insufficiency (POI) is a major cause of reduced female fertility and affects approximately 1% women under 40 years of age. Recent advances emphasize the genetic heterogeneity of POI. Fanconi anemia (FA) genes, traditionally known for their essential roles in DNA repair and cytogenetic instability, have been demonstrated to be involved in meiosis and germ cell development. Here, we conducted whole-exome sequencing (WES) in 50 Han Chinese female patients with POI. Rare missense variants were identified in FANCA (Fanconi anemia complementation group A): c.1772G > A (p.R591Q) and c.3887A > G (p.E1296G). Both variants are heterozygous in the patients and very rare in the human population. In vitro functional studies further demonstrated that these two missense variants of FANCA exhibited reduced protein expression levels compared with the wild type, suggesting the partial loss of function. Moreover, mono-ubiquitination levels of FANCD2 upon mitomycin C stimulation were significantly reduced in cells overexpressing FANCA variants. Furthermore, a loss-of-function mutation of Fanca was generated in C57BL/6 mice for in vivo functional assay. Consistently, heterozygous mutated female mice (Fanca+/−) showed reduced fertility and declined numbers of follicles with aging when compared with the wild-type female mice. Collectively, our results suggest that heterozygous pathogenic variants in FANCA are implicated in non-syndromic POI in Han Chinese women, provide new insights into the molecular mechanisms of POI and highlight the contribution of FANCA variants in female subfertility.Electronic supplementary materialThe online version of this article (10.1007/s00439-019-02059-9) contains supplementary material, which is available to authorized users.

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“…Mutations in STAG3 (stromal antigen 3), which encodes a subunit of the cohesin complex participating to sister chromatid pairing during meiosis, have been identified as a rare POI monogenic cause. To date STAG3 biallelic variants have been reported in seven families worldwide, five of which were consanguineous pedigree (6,(14)(15)(16)(17)(18)(19). All the affected women had isolated POI except for a patient belonging to a Palestinian family (6) who presented simultaneous bilateral ovarian tumors.…”

Section: Introductionmentioning

confidence: 99%

A Long contiguous stretches of homozygosity disclosed a novel biallelic pathogenic variant in STAG3 causing Primary Ovarian Insufficiency

Mellone¹,

Zavattaro²,

Vurchio³

et al. 2021

Preprint

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Background: Primary ovarian insufficiency (POI) refers to an etiologically heterogeneous disorder characterized by hypergonadotropic hypogonadism that represents a major cause of infertility in women under 40 years. Most cases of isolated POI still appear sporadically, but ∼10–15% have an affected first-degree relative, indicating a significant genetic etiology. Several genes implicated in development, meiosis, hormonal signaling and metabolism are involved in the genetic form of the disorder in both syndromic and isolated POI. However, most cases of POI remain unsolved even after exhaustive investigation. Results: Here is reported a 19-year-old Senegalese female affected by non-syndromic POI showing primary amenorrhoea, who well answered to the hormonal induction of puberty reaching a complete sexual maturation in two years. In order to investigate the presence of a genetic defect, aCGH-SNP analysis was performed. A 13.5 Mb long contiguous stretch of homozygosity (LCSH) region on chromosome 7q21.13-q22.1 was identified where the exome sequencing revealed a novel homozygous 4-bp deletion (c.3381_3384delAGAA) in STAG3 . Pathogenic variants in this gene, encoding for a meiosis-specific protein, have been previously reported as cause POI in only seven families and recently as cause of infertility in a male. The here identified mutation leads to the truncation of the last 55 aminoacids, confirming the important role in meiosis of the STAG3 C-terminal domain. Conclusions: In conclusion we identified a loss of function variant in STAG3 in a Senegalese woman with POI reinforcing the role the cohesin complex in the genetic etiology of this disorder. This gene should be included in the screening of POI to offer a better genetic counseling and long term follow-up considering the risk of ovarian tumor in woman carrying pathogenic variants in genes involved in germ cell differentiation.

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A STAG3 missense mutation in two sisters with primary ovarian insufficiency

Cited by 24 publications

References 5 publications

In-Frame Variants in STAG3 Gene Cause Premature Ovarian Insufficiency

In-Frame Variants in STAG3 Gene Cause Premature Ovarian Insufficiency

Rare variants in FANCA induce premature ovarian insufficiency

A Long contiguous stretches of homozygosity disclosed a novel biallelic pathogenic variant in STAG3 causing Primary Ovarian Insufficiency

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