Fundamental role of BMP15 in human ovarian folliculogenesis revealed by null and missense mutations associated with primary ovarian insufficiency

2020 ◽  
Vol 41 (5) ◽  
pp. 983-997 ◽  
Author(s):  
Raffaella Rossetti ◽  
Ilaria Ferrari ◽  
Ilaria Bestetti ◽  
Silvia Moleri ◽  
Francesco Brancati ◽  
...  
Keyword(s):  
Primary Ovarian Insufficiency ◽  
Missense Mutations ◽  
Ovarian Insufficiency ◽  
Ovarian Folliculogenesis

scholarly journals Identification of Multiple Gene Mutations Accounts for a new Genetic Architecture of Primary Ovarian Insufficiency

2016 ◽  
Vol 101 (12) ◽  
pp. 4541-4550 ◽  
Author(s):  
Justine Bouilly ◽  
Isabelle Beau ◽  
Sara Barraud ◽  
Valérie Bernard ◽  
Kemal Azibi ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Gene Mutations ◽  
Primary Ovarian Insufficiency ◽  
Potential Candidate ◽  
Missense Mutations ◽  
Ovarian Insufficiency ◽  
Monogenic Disorder ◽  
Gene Encoding ◽  
Multiple Loci

Context: Idiopathic primary ovarian insufficiency (POI) is a major cause of amenorrhea and infertility. POI affects 1% of women before age 40 years, and several genetic causes have been reported. To date, POI has been considered a monogenic disorder. Objective: The aim of this study was to identify novel gene variations and to investigate if individuals with POI harbor mutation in multiple loci. Patients and Methods: One hundred well-phenotyped POI patients were systematically screened for variants in 19 known POI loci (and potential candidate genes) using next-generation sequencing. Results: At least one rare protein-altering gene variant was identified in 19 patients, including missense mutations in new candidate genes, namely SMC1β and REC8 (involved in the cohesin complex) and LHX8, a gene encoding a transcription factor. Novel or recurrent deleterious mutations were also detected in the known POI candidate genes NOBOX, FOXL2, SOHLH1, FIGLA, GDF9, BMP15, and GALT. Seven patients harbor mutations in two loci, and this digenicity seems to influence the age of symptom onset. Conclusions: Genetic anomalies in women with POI are more frequent than previously believed. Digenic findings in several cases suggest that POI is not a purely monogenic disorder and points to a role of digenicity. The genotype-phenotype correlations in some kindreds suggest that a synergistic effect of several mutations may underlie the POI phenotype.

scholarly journals Primary ovarian insufficiency in classic galactosemia: role of FSH dysfunction and timing of the lesion

2012 ◽  
Vol 36 (1) ◽  
pp. 29-34 ◽  
Author(s):  
Cynthia S. Gubbels ◽  
Jolande A. Land ◽  
Johannes L. H. Evers ◽  
Jörgen Bierau ◽  
Paul P. C. A. Menheere ◽  
...  
Keyword(s):  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Classic Galactosemia

Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology

2018 ◽  
Vol 40 (1) ◽  
pp. 25-30 ◽  
Author(s):  
Liliana C. Patiño ◽  
Isabelle Beau ◽  
Adrien Morel ◽  
Brigitte Delemer ◽  
Jacques Young ◽  
...  
Keyword(s):  
Primary Ovarian Insufficiency ◽  
Missense Mutations ◽  
Ovarian Insufficiency

BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency

2019 ◽  
Vol 105 (4) ◽  
pp. e1449-e1457 ◽  
Author(s):  
Lucie Renault ◽  
Liliana C Patiño ◽  
Françoise Magnin ◽  
Brigitte Delemer ◽  
Jacques Young ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Chromosomal Abnormalities ◽  
Primary Ovarian Insufficiency ◽  
Bone Morphogenic Protein ◽  
Bmp Signaling ◽  
Pathophysiological Mechanism ◽  
Missense Mutations ◽  
Ovarian Insufficiency ◽  
The Impact

Abstract Context Primary ovarian insufficiency (POI) is a frequently occurring disorder affecting approximately 1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone, leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene mutations, most cases remain idiopathic. Objective To identify and to functionally validate new sequence variants in 2 genes that play a key role in mammalian ovarian function, BMPR1A and BMPR1B (encoding for bone morphogenic protein receptor), leading to POI. Methods The impact on bone morphogenic protein (BMP) signaling of BMPR1A and BMPR1B variants, previously identified by whole-exome sequencing on 69 women affected by isolated POI, was established by different in vitro functional experiments. Results We demonstrate that the BMPR1A-p.Arg442His and BMPR1B-p.Phe272Leu variants are correctly expressed and located but lead to an impairment of downstream BMP signaling. Conclusion In accordance with infertility observed in mice lacking Bmpr1a in the ovaries and in Bmpr1b-/- mice, our results unveil, for the first time, a link between BMPR1A and BMPR1B variants and the origin of POI. We show that BMP signaling impairment through specific BMPR1A and BMPR1B variants is a novel pathophysiological mechanism involved in human POI. We consider that BMPR1A and BMPR1B variants constitute genetic biomarkers of the origin of POI and have clinical utility.

scholarly journals Role of inflammation and oxidative stress in the etiology of primary ovarian insufficiency

2016 ◽  
Vol 13 (3) ◽  
pp. 109-115 ◽  
Author(s):  
Elif Ağaçayak ◽  
Neval Yaman Görük ◽  
Hakan Küsen ◽  
Senem Yaman Tunç ◽  
Serdar Başaranoğlu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
And Oxidative Stress

P–577 Impaired double strand DNA repair in isolated Primary Ovarian Insufficiency with homozygous nonsense mutation of SPIDR

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
A Heddar ◽  
N Guichoux ◽  
N Auger ◽  
M Misrahi
Keyword(s):  
Dna Repair ◽  
Nonsense Mutation ◽  
Chromosomal Instability ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Damage Repair ◽  
Cytogenetic Studies ◽  
Homozygous Nonsense Mutation ◽  
Double Strand Dna

Abstract Study question To identify the etiology of isolated Primary Ovarian Insufficiency (POI) in a patient from an Indian consanguineous family. Summary answer A homozygous nonsense mutation of SPIDR in the patient yielded chromosomal instability: first evidence of a role of this gene in DNA repair. What is known already POI, affecting 1% of women under 40, is a public health problem. To date ∼ 70% of cases remain idiopathic. The leap due to exome sequencing, led to the identification of ∼ 80 genes, often in single or few cases. SPIDR was recently identified as a scaffolding protein connecting RAD51, a central player in homologous recombination, to BLM, a helicase implicated in the integrity of the genome. But its precise role is still unknown. A SPIDR mutation was previously associated with POI. However, contradictory conclusions were reported on the mechanism of SPIDR action and on its pathogenic role in POI. Study design, size, duration Prospective genetic study of a cohort of 150 pateints with POI worldwide using a custom-made targeted next generation sequencing (NGS) panel comprising 60 known POI-causing genes. A single patient was found mutated in SPIDR. Cytogenetic studies were performed to analyse the consequences of the mutation on DNA repair and sister chromatide exchanges (SCE). Participants/materials, setting, methods The patient with SPIDR mutation had POI with primary amenorrhea, delayed puberty and streaks ovaries. She was born to consanguineous Indian parents. No other mutation was detected in our cohort of 150 patients with POI. Targeted NGS was performed in the proposita. Familial segregation was performed by Sanger sequencing. Mitomycin C (MMC)-induced chromosomal breakages were studied and a sister chromatid exchange (SCE) assay was performed in patient’s peripheral lymphocytes. Main results and the role of chance We identified a novel homozygous nonsense mutation in the exon 7 of SPIDR (KIAA0146) c.814C>T, R272*, predicted to yield either a truncated protein, or a non-sense-mediated mRNA decay. The patient’s cells display increased chromosomal fragility with high MMC-induced chromosomal breaks when compared to a control. Remarkably, there was no increased SCE. In the previous report of a SPIDR mutation in POI, no cytogenetic studies were performed, and contradictory results were obtained on a homologous recombination test between the two sisters, either enhanced or reduced. In conclusion, we show here that inactivation of SPIDR results in a defect of double strand DNA damage repair, similar to alteration of the RAD51 pathway. There was no increased SCE, the hallmark of the BLM pathway. This observation has major consequences for this patient’s care : indeed mutations of DNA-repair genes may also yield to tumors/cancers. A long follow-up of the patient is needed in a multidisciplinary team to detect possible comorbidities. Indeed, even in the absence of somatic symptomatology, the patient has enhanced chromosomal instability highlighted by cytogenetic studies, that may yield tumor-predisposition. Limitations, reasons for caution No other mutation of SPIDR in the replication cohort of 150 POI patients. SPIDR mutation are thus very rare world-wide. Wider implications of the findings: This is the first evidence of chromosomal instability associated with SPIDR defect, providing strong evidence for a role of SPIDR in double strand DNA damage repair in humans and for its causal role in POI. Our study improves the knowledge on SPIDR function and confirms its involvement in POI worldwide. Trial registration number Not applicable

scholarly journals BRCA1, BRCA2 and primary ovarian insufficiency

2020 ◽  
Vol 165 ◽  
pp. 05009
Author(s):  
Yinuo Zhang
Keyword(s):  
Primary Ovarian Insufficiency ◽  
Dna Breaks ◽  
Brca1 And Brca2 ◽  
Dsb Repair ◽  
Ovarian Insufficiency ◽  
Ovarian Aging ◽  
Brca Genes ◽  
Mutation Carriers ◽  
Increased Risk

BRCA1 and BRCA2 genes belong to the family of ataxia-telangiectasia-mutated (ATM)-mediated DNA DSB repair genes that play a critical role in the DNA double-strand break (DSB) repair. Mutations in BRCA genes significantly increase the lifetime risk of breast, ovarian, fallopian tube and primary peritoneal cancers. In addition to the increased risk for multiple malignancies, recent literature suggest that mutations in BRCA genes could lead to decreased ovarian reserve and subsequent ovarian aging. In this review, we will focus on role of BRCA1 and BRCA2 in ovarian function, particularly ovarian aging and primary ovarian insufficiency. Serum AMH values are generally lower in BRCA1 mutation carriers but not in BRCA2 mutation carriers. BRCA2 carriers were more likely to have chemotherapy-induced amenorrhea DNA not stable, linking with ovarian aging. The mechanism by which BRCAs mutation in the pathogenesis of POI is the inpaired function of repairing DNA breaks. Future studies investigating the knockout models to elucidate the role of the BRCAs genes in ovarian development and oocyte maturation will be interesting.

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