BRCA mutations and reproduction

Daum, Hagit; Peretz, Tamar; Laufer, Neri

doi:10.1016/j.fertnstert.2017.12.004

Cited by 57 publications

(37 citation statements)

References 59 publications

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“…The only remaining 727 variant was the BRCA2 missense mutation detected in the propositus (our patient, Figure 1, 728 V2), BRCA2: c. c.8524C>T; p. Arg2842Cys. 729 BRCA2 heterozygous mutations were associated with lower AMH levels, reflecting the ovarian 730 reserve (Daum et al, 2018). We cannot exclude that the heterozygous R2842C-BRCA2 731 mutation could have an impact on the mother's ovarian reserve in addition to environmental 732 factors.…”

Section: Real-time Quantitative Pcr 436mentioning

confidence: 93%

A homozygous hypomorphic BRCA2 variant causes primary ovarian insufficiency without cancer or Fanconi anemia traits

Caburet

Heddar

Dardillac

et al. 2019

Preprint

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25Primary Ovarian insufficiency (POI) affects 1% of women under forty. We studied a patient 26 with a non-syndromic POI, from a consanguineous Turkish family. Exome sequencing 27 identified a homozygous missense variant c.8524C>T/p.R2842C in BRCA2. BRCA2 is a major 28 player in homologous recombination (HR). BRCA2 deficiency induces cancer predisposition 29 and Fanconi Anemia (FA). Remarkably, neither the patient nor her family exhibit somatic 30 pathologies. The patient's somatic cells presented intermediate levels of chromosomal breaks, 31 cell proliferation and radiation-induced RAD51 foci formation when compared to controls, the 32 heterozygous mother's and FA cells. R2842C-BRCA2 partially complemented BRCA2 33 depletion for double-strand break-induced HR. The residual HR function in patient's cells could 34 explain the absence of somatic pathology. BRCA2 is expressed in human fetal ovaries in 35 pachytene stage oocytes, when meiotic HR occurs. This study has a major impact on the 36 understanding of genome maintenance in somatic and meiotic cells and on the management of 37 POI patients. 38 39 Keywords: BRCA2 / mutation / cancer / Fanconi anemia / Primary ovarian insufficiency / 40 meiosis. 41 42

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Section: Real-time Quantitative Pcr 436mentioning

confidence: 93%

A homozygous hypomorphic BRCA2 variant causes primary ovarian insufficiency without cancer or Fanconi anemia traits

Caburet

Heddar

Dardillac

et al. 2019

Preprint

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“…Thus, the function and expression level of BRCA2 is vital in germ cells and regulating the BRCA2 expression level is important for meiosis and maintaining DNA integrity. However, in humans, relationships between BRCA2 mutations and fertility have been controversial [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Reduced translation efficiency due to novel splicing variants in 5′ untranslated region and identification of novel cis-regulatory elements in canine and human BRCA2

Yoshikawa

Morimatsu²,

Kozuma

et al. 2020

Preprint

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Background Breast cancer 2, early onset (BRCA2) is a tumor suppressor gene. The protein encoded by this gene plays an important role in homologous recombination (HR)-mediated DNA repair. Deleterious mutations in BRCA2 and downregulation of its expression have been associated with tumorigenesis in dogs and humans. Thus, regulation of BRCA2 expression level is important for maintaining homeostasis in homologous recombination. Results In this study, the mechanisms that regulate the expression of BRCA2 were proposed. Novel splicing variants were identified in the 5′ untranslated region (UTR) of canine and human BRCA2 in canine testis, canine ovary, and canine and human cultured cell lines. In cultured cells, the ratio of BRCA2 splicing variants at 5′ UTR was altered by serum starvation. These novel splicing variants, excluding one of the canine splicing variants, were found to reduce the translational efficiency. Additionally, the DNA sequence in human BRCA2 intron 1 harbored novel cis-regulatory elements. Three silencer and two enhancer cis-regulatory elements were identified in human BRCA2 intron 1. Conclusions This study demonstrates that BRCA2 expression level is regulated via 5′ UTR splicing variants and that the BRCA2 intron 1 region harbors cis-regulatory elements.

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“…Moreover, compared to similar women without cancer, even women with apparently preserved ovarian function after chemotherapy are more likely to experience infertility as well as less success from ART cycles with autologous oocytes 5,6 . This is compounded in this patient population by the fact that some mutations which predispose women to cancer, such as BRCA1 and Fanconi Anemia pathway members, are also associated with premature ovarian insufficiency 7,8 .…”

Section: Introductionmentioning

confidence: 99%

iPSC-Derived Ovarian Tissue Restores Ovarian Function in Subfertile Mice and After Gonadotoxic Chemotherapy

Elias

et al. 2019

Preprint

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Running Title: iPSC-based restoration of ovarian function following gonadotoxic chemotherapy iPSC -based restoration of ovarian function following gonadotoxic chemotherapy 2 Abstract Many oncologic therapies given to young women are gonadotoxic and associated with diminished ovarian reserve, increased risk of permanent sterility, and premature menopause. Previously, we reported the derivation of steroidogenic ovarian cells from induced pluripotent and embryonic stem cells. Derived cells not only produced reproductive hormones, but also displayed markers of ovarian tissue and primordial gametes. Here, we describe that human follicular fluid, when added to our stem cell differentiation system, enhances the steroidogenic potential of derived cells and increases the subpopulation of cells that differentiate to express the ovarian and germ cell markers GJA1 and ZP1, respectively. More importantly, using an in vivo model of chemotherapy-induced premature ovarian insufficiency in subfertile nude mice, we demonstrate that orthotopic implantation of these derived cells restores ovarian hormonal production and produces functional stem cell-derived germ cells. Collectively, these data support the hypothesis that stem cell-derived steroidogenic ovarian tissue could be used to promote neo-gametogenesis and treat premature menopause.iPSC -based restoration of ovarian function following gonadotoxic chemotherapy

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BRCA mutations and reproduction

Cited by 57 publications

References 59 publications

A homozygous hypomorphic BRCA2 variant causes primary ovarian insufficiency without cancer or Fanconi anemia traits

A homozygous hypomorphic BRCA2 variant causes primary ovarian insufficiency without cancer or Fanconi anemia traits

Reduced translation efficiency due to novel splicing variants in 5′ untranslated region and identification of novel cis-regulatory elements in canine and human BRCA2

iPSC-Derived Ovarian Tissue Restores Ovarian Function in Subfertile Mice and After Gonadotoxic Chemotherapy

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