scholarly journals Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation

2017 ◽  
Vol 103 (2) ◽  
pp. 555-563 ◽  
Author(s):  
Abdulmoein Eid Al-Agha ◽  
Ihab Abdulhamed Ahmed ◽  
Esther Nuebel ◽  
Mika Moriwaki ◽  
Barry Moore ◽  
...  
Keyword(s):  
Protein Localization ◽  
Pubertal Development ◽  
Recessive Gene ◽  
Missense Variant ◽  
Primary Ovarian Insufficiency ◽  
Delayed Puberty ◽  
Primary Amenorrhea ◽  
Ovarian Insufficiency ◽  
Functional Studies ◽  
Exon 1

Abstract Context The etiology of primary ovarian insufficiency (POI) remains unknown in most cases. Objective We sought to identify the genes causing POI. Design The study was a familial genetic study. Setting The study was performed at two academic institutions. Patients We identified a consanguineous Yemeni family in which four daughters had POI. A brother had azoospermia. Intervention DNA was subjected to whole genome sequencing. Shared regions of homozygosity were identified using Truploidy and prioritized using the Variant Annotation, Analysis, and Search Tool with control data from 387 healthy subjects. Imaging and quantification of protein localization and mitochondrial function were examined in cell lines. Main Outcome Homozygous recessive gene variants shared by the four sisters. Results The sisters shared a homozygous stop gain mutation in exon 6 of PSMC3IP (c.489 C>G, p.Tyr163Ter) and a missense variant in exon 1 of CLPP (c.100C>T, p.Pro34Ser). The affected brother also carried the homozygous PSMC3IP mutation. Functional studies demonstrated mitochondrial fragmentation in cells infected with the CLPP mutation. However, no abnormality was found in mitochondrial targeting or respiration. Conclusions The PSMC3IP mutation provides additional evidence that mutations in meiotic homologous recombination and DNA repair genes result in distinct female and male reproductive phenotypes, including delayed puberty and primary amenorrhea caused by POI (XX gonadal dysgenesis) in females but isolated azoospermia with normal pubertal development in males. The findings also suggest that the N-terminal missense mutation in CLPP does not cause substantial mitochondrial dysfunction or contribute to ovarian insufficiency in an oligogenic manner.

scholarly journals Menarche in primary ovarian insufficiency after a month of hormone replacement therapy: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Biwen Cheng
Keyword(s):  
Replacement Therapy ◽  
Hormone Replacement ◽  
Estrogen Therapy ◽  
Primary Ovarian Insufficiency ◽  
Hormonal Replacement Therapy ◽  
Delayed Puberty ◽  
Ovarian Insufficiency ◽  
Breakthrough Bleeding ◽  
Hormonal Replacement ◽  
Ovarian Dysgenesis

Abstract Background Gynecologic anomalies, including uterine agenesis and ovarian dysgenesis, are some of the several differential diagnoses in adolescent females with primary amenorrhea and delayed puberty. Primary ovarian insufficiency is reported in the clinical practice of reproductive endocrinology can be determined by conducting sex hormone tests to evaluate the hypothalamic-pituitary-ovarian axis. However, confirmation of Mullerian agenesis by image modalities can be extremely challenging. Once the diagnosis is established, breakthrough bleeding usually occurs 2 to 3 years after hormonal replacement therapy. Case presentation We report a case of a seventeen year old Taiwanese female, 46 XX karyotype, with ovarian dysgenesis and an initial tentative diagnosis of uterine agenesis who experienced a breakthrough bleeding after a month of hormonal replacement therapy. Conclusions The breakthrough bleeding after a month of estrogen therapy in primary ovarian insufficiency is uncommon, and the diagnosis of the absent uterus can have an extensive psychological impact on patients and their families.

scholarly journals Homozygous Inactivating Mutation inNANOS3in Two Sisters with Primary Ovarian Insufficiency

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Mariza G. Santos ◽  
Aline Z. Machado ◽  
Conceição N. Martins ◽  
Sorahia Domenice ◽  
Elaine M. F. Costa ◽  
...  
Keyword(s):  
Rna Binding ◽  
Mutational Analysis ◽  
Primordial Germ Cells ◽  
Embryonic Cell ◽  
Primary Ovarian Insufficiency ◽  
Primary Amenorrhea ◽  
Female Reproduction ◽  
Ovarian Insufficiency ◽  
Rna Interaction

Despite the increasing understanding of female reproduction, the molecular diagnosis of primary ovarian insufficiency (POI) is seldom obtained. The RNA-binding protein NANOS3 poses as an interesting candidate gene for POI since members of the Nanos family have an evolutionarily conserved function in germ cell development and maintenance by repressing apoptosis. We performed mutational analysis ofNANOS3in a cohort of 85 Brazilian women with familial or isolated POI, presenting with primary or secondary amenorrhea, and in ethnically-matched control women. A homozygous p.Glu120Lys mutation inNANOS3was identified in two sisters with primary amenorrhea. The substituted amino acid is located within the second C2HC motif in the conserved zinc finger domain of NANOS3 andin silicomolecular modelling suggests destabilization of protein-RNA interaction.In vitroanalyses of apoptosis through flow cytometry and confocal microscopy show that NANOS3 capacity to prevent apoptosis was impaired by this mutation. The identification of an inactivating missense mutation inNANOS3suggests a mechanism for POI involving increased primordial germ cells (PGCs) apoptosis during embryonic cell migration and highlights the importance of NANOS proteins in human ovarian biology.

scholarly journals Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice

2020 ◽  
Vol 26 (7) ◽  
pp. 485-497
Author(s):  
Diego Hernández-López ◽  
Adriana Geisinger ◽  
María Fernanda Trovero ◽  
Federico F Santiñaque ◽  
Mónica Brauer ◽  
...  
Keyword(s):  
Mouse Model ◽  
Central Element ◽  
Transcript Level ◽  
Primary Ovarian Insufficiency ◽  
Primary Amenorrhea ◽  
Causative Role ◽  
Ovarian Insufficiency ◽  
Humanized Mouse Model ◽  
Chromosome Synapsis ◽  
Human Mutation

Abstract More than 50% of cases of primary ovarian insufficiency (POI) and nonobstructive azoospermia in humans are classified as idiopathic infertility. Meiotic defects may relate to at least some of these cases. Mutations in genes coding for synaptonemal complex (SC) components have been identified in humans, and hypothesized to be causative for the observed infertile phenotype. Mutation SYCE1 c.721C>T (former c.613C>T)—a familial mutation reported in two sisters with primary amenorrhea—was the first such mutation found in an SC central element component-coding gene. Most fundamental mammalian oogenesis events occur during the embryonic phase, and eventual defects are identified many years later, thus leaving few possibilities to study the condition’s etiology and pathogenesis. Aiming to validate an approach to circumvent this difficulty, we have used the CRISPR/Cas9 technology to generate a mouse model with an SYCE1 c.721C>T equivalent genome alteration. We hereby present the characterization of the homozygous mutant mice phenotype, compared to their wild type and heterozygous littermates. Our results strongly support a causative role of this mutation for the POI phenotype in human patients, and the mechanisms involved would relate to defects in homologous chromosome synapsis. No SYCE1 protein was detected in homozygous mutants and Syce1 transcript level was highly diminished, suggesting transcript degradation as the basis of the infertility mechanism. This is the first report on the generation of a humanized mouse model line for the study of an infertility-related human mutation in an SC component-coding gene, thus representing a proof of principle.

scholarly journals A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP

2020 ◽  
Author(s):  
Natalia Felipe-Medina ◽  
Sandrine Caburet ◽  
Fernando Sánchez-Sáez ◽  
Yazmine B. Condezo ◽  
Dirk de Rooij ◽  
...  
Keyword(s):  
Missense Variant ◽  
Primary Ovarian Insufficiency ◽  
Dna Breaks ◽  
Ovarian Insufficiency ◽  
Knock Out ◽  
Recombination Nodules ◽  
Meiotic Gene ◽  
Double Strand Dna Breaks ◽  
Gene Functional Analysis

AbstractPrimary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with 3 cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse, compared to a new HSF2BP knock-out mouse showed that it behaves as a hypomorphic allele. HSF2BP-S167L females show reduced fertility with small litter sizes. To obtain mechanistic insights, we identified C19ORF57/MIDAP as a strong interactor and stabilizer of HSF2BP by forming a higher-order macromolecular structure involving BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L mutation showed a strongly decreased expression of both MIDAP and HSF2BP at the recombination nodules. Although HSF2BP-S167L does not affect heterodimerization between HSF2BP and MIDAP, it promotes a lower expression of both proteins and a less proficient activity in replacing RPA by the recombinases RAD51/DMC1, thus leading to a lower frequency of cross-overs. Our results provide insights into the molecular mechanism of two novel actors of meiosis underlying non-syndromic ovarian insufficiency.SummaryFelipe-Medina et al. describe a missense variant in the meiotic gene HSF2BP in a consanguineous family with Premature Ovarian Insufficiency, and characterize it as an hypormorphic allele, that in vivo impairs its dimerization with a novel meiotic actor, MIDAP/ C19ORF57, and affect recombination at double-strand DNA breaks.

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

2019 ◽  
Author(s):  
Sandrine Caburet ◽  
Abdelkader Heddar ◽  
Elodie Dardillac ◽  
Helene Creux ◽  
Marie Lambert ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Missense Variant ◽  
Strand Break ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Her Family ◽  
Major Player ◽  
Chromosomal Breaks ◽  
Turkish Family ◽  
Radiation Induced

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

Variants in Homologous Recombination Genes EXO1 and RAD51 Related with Premature Ovarian Insufficiency

2020 ◽  
Vol 105 (10) ◽  
pp. e3566-e3574
Author(s):  
Wei Luo ◽  
Ting Guo ◽  
Guangyu Li ◽  
Ran Liu ◽  
Shidou Zhao ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Budding Yeast ◽  
Protein Localization ◽  
Elevated Serum ◽  
Human Cell Line ◽  
Human Cells ◽  
Premature Ovarian Insufficiency ◽  
Primary Amenorrhea ◽  
Ovarian Insufficiency

Abstract Context Premature ovarian insufficiency (POI) is characterized by cessation of menstruation before 40 years of age and elevated serum level of FSH (>25 IU/L). Recent studies have found a few causative genes responsible for POI enriched in meiotic recombination and DNA damage repair pathways. Objective To investigate the role of variations in homologous recombination genes played in POI pathogenesis. Methods The whole exome sequencing was performed in 50 POI patients with primary amenorrhea. Functional characterizations of the novel variants were carried out in budding yeast and human cell line. Results We identified 8 missense variants in 7 homologous recombination genes, including EXO1, RAD51, RMI1, MSH5, MSH2, MSH6, and MLH1. The mutation p.Thr52Ser in EXO1 impaired the meiotic process of budding yeast and p.Glu68Gly in RAD51-altered protein localization in human cells, both of them impaired the efficiency of homologous recombination repair for DNA double-stranded breaks in human cells. Conclusions Our study first linked the variants of EXO1 and RAD51 with POI and further highlighted the role of DNA repair genes in ovarian dysgenesis.

scholarly journals Homozygous hypomorphic BRCA2 variant in primary ovarian insufficiency without cancer or Fanconi anaemia trait

2020 ◽  
pp. jmedgenet-2019-106672 ◽  
Author(s):  
Sandrine Caburet ◽  
Abdelkader Heddar ◽  
Elodie Dardillac ◽  
Héléne Creux ◽  
Marie Lambert ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Public Health Problem ◽  
Chromosome Breakage ◽  
Primary Ovarian Insufficiency ◽  
Fanconi Anaemia ◽  
Ovarian Insufficiency ◽  
Her Family ◽  
Functional Studies ◽  
Chromosomal Breaks ◽  
Radiation Induced

BackgroundPrimary ovarian insufficiency (POI) affects 1% of women under 40 years and is a public health problem. The genetic causes of POI are highly heterogeneous with isolated or syndromic forms. Recently, variants in genes involved in DNA repair have been shown to cause POI. Notably, syndromic POI with Fanconi anaemia (FA) traits related to biallelic BRCA2 truncated variants has been reported. Here, we report a novel phenotype of isolated POI with a BRCA2 variant in a consanguineous Turkish family.MethodsExome sequencing (ES) was performed in the patient. We also performed functional studies, including a homologous recombination (HR) test, cell proliferation, radiation-induced RAD51 foci formation assays and chromosome breakage studies in primary and lymphoblastoid immortalised cells. The expression of BRCA2 in human foetal ovaries was studied.ResultsES identified a homozygous missense c.8524C>T/p.R2842C-BRCA2 variant. BRCA2 defects induce cancer predisposition and FA. Remarkably, neither the patient nor her family exhibited somatic pathologies. The patient’s cells showed intermediate levels of chromosomal breaks, cell proliferation and radiation-induced RAD51 foci formation compared with controls and FA cells. R2842C-BRCA2 only partially complemented HR efficiency compared with wild type-BRCA2. BRCA2 is expressed in human foetal ovaries in pachytene stage oocytes, when meiotic HR occurs.ConclusionWe describe the functional assessment of a homozygous hypomorphic BRCA2 variant in a patient with POI without cancer or FA trait. Our findings extend the phenotype of BRCA2 biallelic alterations to fully isolated POI. This study has a major impact on the management and genetic counselling of patients with POI.

A Novel Phenotype Combining Primary Ovarian Insufficiency Growth Retardation and Pilomatricomas With MCM8 Mutation

2020 ◽  
Vol 105 (6) ◽  
pp. 1973-1982 ◽  
Author(s):  
Abdelkader Heddar ◽  
Dominique Beckers ◽  
Baptiste Fouquet ◽  
Dominique Roland ◽  
Micheline Misrahi
Keyword(s):  
Growth Retardation ◽  
Genetic Defect ◽  
Postnatal Growth ◽  
Primary Ovarian Insufficiency ◽  
Primary Amenorrhea ◽  
Dna Breaks ◽  
Ovarian Insufficiency ◽  
Messenger Ribonucleic Acid ◽  
Adverse Health Outcomes ◽  
Chromosomal Breaks

Abstract Context Primary Ovarian insufficiency (POI) affects 1% of women aged <40 years and leads most often to definitive infertility with adverse health outcomes. Very recently, genes involved in deoxyribonucleic acid (DNA) repair have been shown to cause POI. Objective To identify the cause of a familial POI in a consanguineous Turkish family. Design Exome sequencing was performed in the proposita and her mother. Chromosomal breaks were studied in lymphoblastoid cell lines treated with mitomycin (MMC). Setting and patients The proposita presented intrauterine and postnatal growth retardation, multiple pilomatricomas in childhood, and primary amenorrhea. She was treated with growth hormone (GH) from age 14 to 18 years. Results We identified a novel nonsense variant in exon 9 of the minichromosome maintenance complex component 8 gene (MCM8) NM_001281522.1: c0.925C > T/p.R309* yielding either a truncated protein or nonsense-mediated messenger ribonucleic acid decay. The variant was homozygous in the daughter and heterozygous in the mother. MMC induced DNA breaks and aberrant metaphases in the patient’s lymphoblastoid cells. The mother’s cells had intermediate but significantly higher chromosomal breaks compared with a control. Conclusion We describe a novel phenotype of syndromic POI related to a novel truncating MCM8 variant. We show for the first time that spontaneous tumors (pilomatricomas) are associated with an MCM8 genetic defect, making the screening of this gene necessary before starting GH therapy in patients with POI with short stature, especially in a familial or consanguineous context. Appropriate familial monitoring in the long term is necessary, and fertility preservation should be considered in heterozygous siblings to avoid rapid follicular atresia.

scholarly journals A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Natalia Felipe-Medina ◽  
Sandrine Caburet ◽  
Fernando Sánchez-Sáez ◽  
Yazmine B Condezo ◽  
Dirk G de Rooij ◽  
...  
Keyword(s):  
Missense Variant ◽  
Primary Ovarian Insufficiency ◽  
Loss Of Function ◽  
Ovarian Insufficiency ◽  
Knock Out ◽  
Recombination Nodules ◽  
Hypomorphic Allele ◽  
Whole Exome ◽  
Gene Functional Analysis ◽  
Knock Out Mouse

Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele compared to a new loss-of-function (knock-out) mouse model. Hsf2bpS167L/S167L females show reduced fertility with smaller litter sizes. To obtain mechanistic insights, we identified C19ORF57/BRME1 as a strong interactor and stabilizer of HSF2BP and showed that the BRME1/HSF2BP protein complex co-immunoprecipitates with BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased staining of both HSF2BP and BRME1 at the recombination nodules and a reduced number of the foci formed by the recombinases RAD51/DMC1, thus leading to a lower frequency of crossovers. Our results provide insights into the molecular mechanism of HSF2BP-S167L in human ovarian insufficiency and sub(in)fertility.

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