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.

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.

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 Human BM-MSC secretome enhances human granulosa cell proliferation and steroidogenesis and restores ovarian function in primary ovarian insufficiency mouse model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hang-soo Park ◽  
Rishi Man Chugh ◽  
Abdeljabar El Andaloussi ◽  
Elie Hobeika ◽  
Sahar Esfandyari ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mouse Model ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Cellular Proliferation ◽  
Ovarian Function ◽  
Human Mesenchymal Stem Cells ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
And Function

AbstractPrimary ovarian insufficiency (POI) is defined as the loss of ovarian function before 40 years of age. It clinically manifests as amenorrhea, infertility, and signs of estrogen insufficiency. POI is frequently induced by chemotherapy. Gonadotoxic chemotherapy reagents damage granulosa cells, which are essential for follicular function and development. Our recently published studies demonstrated that intraovarian transplantation of human mesenchymal stem cells (hMSCs) can restore fertility in a chemotherapy-induced POI mouse model. However, the regenerative mechanism underlying the hMSC effect in POI mice is not fully understood. Here, we report that the hMSC secretome increased the proliferation of human granulosa cells (HGrC1). We showed by FACS analysis that treatment of HGrC1 cells with hMSC-conditioned media (hMSC CM) stimulates cellular proliferation. We also demonstrated that the expression of steroidogenic enzymes involved in the production of estrogen, CYP19A1 and StAR, are significantly elevated in hMSC CM-treated HGrC1 cells. Our data suggest that hMSC CM stimulates granulosa cell proliferation and function, which may explain the therapeutic effect of hMSCs in our chemotherapy-induced POI animal model. Our findings indicate that the hMSC secretome may be a novel treatment approach for restoring granulosa cell and ovarian function in 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.

Demographic characteristics and therapeutical management in patients with primary ovarian insufficiency

2014 ◽  
Author(s):  
Mariana Tome ◽  
Pinillos Guillermo Martinez De ◽  
Mariola Mendez ◽  
Quiros Juan Manuel Garcia De ◽  
Jose Ignacio Fernandez Pena ◽  
...  
Keyword(s):  
Primary Ovarian Insufficiency ◽  
Demographic Characteristics ◽  
Ovarian Insufficiency

scholarly journals Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Mendy M Welsink-Karssies ◽  
Sacha Ferdinandusse ◽  
Gert J Geurtsen ◽  
Carla E M Hollak ◽  
Hidde H Huidekoper ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Newborn Screening ◽  
Clinical Outcomes ◽  
Movement Disorders ◽  
Brain Mri ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Classical Galactosemia ◽  
Intellectual Outcome

Abstract Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P < 0.0005). Qualitative analysis of the MRI’s demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.

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.

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