16 results on '"Ozlem Okutman"'
Search Results
2. Evaluation of a Custom Design Gene Panel as a Diagnostic Tool for Human Non-Syndromic Infertility
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Ozlem Okutman, Julien Tarabeux, Jean Muller, and Stéphane Viville
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custom design panel ,high-throughput sequencing ,non-syndromic human infertility ,DNA ,Genetics ,QH426-470 - Abstract
Infertility is a global healthcare problem, which affects men and women equally. With the advance of genome-wide analysis, an increasing list of human genes involved in infertility is now available. In order to evaluate the diagnostic interest to analyze these genes, we have designed a gene panel allowing the analysis of 51 genes involved in non-syndromic human infertility. In this initial evaluation study, a cohort of 94 non-syndromic infertility cases with a well-defined infertility phenotype was examined. Five patients with previously known mutations were used as positive controls. With a mean coverage of 457×, and 99.8% of target bases successfully sequenced with a depth coverage over 30×, we prove the robustness and the quality of our panel. In total, we identified pathogenic or likely pathogenic variations in eight patients (five male and three female). With a diagnostic yield of 8.5% and the identification of a variety of variants including substitution, insertion, deletion, and copy number variations, our results demonstrate the usefulness of such a strategy, as well as the efficiency and the quality of this diagnostic gene panel.
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- 2021
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3. A biallelic loss of function variant in HORMAD1 within a large consanguineous Turkish family is associated with spermatogenic arrest
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Ozlem Okutman, Manon Boivin, Jean Muller, Nicolas Charlet-Berguerand, and Stéphane Viville
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Reproductive Medicine ,Rehabilitation ,Obstetrics and Gynecology - Abstract
STUDY QUESTION Can the analysis of a large Turkish consanguineous family via whole exome sequencing (WES) identify novel causative genetic variation responsible for nonobstructive azoospermia (NOA) characterized by arrest at primary spermatocyte stage? SUMMARY ANSWER WES analysis revealed a homozygous nonsense variant in HORMAD1 in three affected brothers of a Turkish family. WHAT IS KNOWN ALREADY Studying patient cohorts in small or large consanguineous families using high-throughput sequencing allows the identification of genetic causes of different pathologies, including infertility. Over the last two decades, a number of genes involved in human male infertility have been discovered, but only 14 genes have been identified as being at least moderately linked to isolated NOA or oligozoospermia in men. STUDY DESIGN, SIZE, DURATION The study included a Turkish family comprising three brothers with NOA. Two brothers had a normal karyotype, normal hormonal levels and no Yq microdeletion. The testicular histopathology analysis revealed the complete arrest of spermatogenesis at the primary spermatocyte stage. PARTICIPANTS/MATERIALS, SETTING, METHODS We recruited a consanguineous Turkish family where parents were first-degree cousins and had seven children; three sons who had NOA, two sons who were fertile and two daughters for whom no information was available. Saliva samples from the index patient, his two affected brothers, parents and two nonaffected brothers (seven samples in total) were collected. Prior to WES, the index patient underwent targeted genetic testing using an infertility panel, which includes 133 infertility genes. No pathogenic variations were identified. WES was then performed on the DNA of the seven family members available. Bioinformatics analysis was performed using an in-house pipeline. Detected variants were scored and ranked, and copy number variants were called and annotated. The consequences of mutation on protein expression and localization were investigated by cell transfection followed by immunofluorescence or immunoblotting. MAIN RESULTS AND THE ROLE OF CHANCE WES revealed a homozygous nonsense variant chr1:150675797G>A; HORMAD1 (NM_032132.5): c.1021C>T, p.Gln341* in exon 13, which was confirmed in all three affected brothers. HORMAD1 encodes the HORMA domain-containing protein 1. The parents as well as the two fertile brothers were carriers of this variant. This variant may lead to the production of a truncated protein lacking the nuclear localization signal; therefore, human cells were transfected with the wild-type and mutated form, in fusion with green fluorescent protein. Immunoblotting experiments confirmed the production of a truncated HORMAD1 protein, and immunofluorescence microscopy revealed that the mutated protein displayed cytoplasmic localization while the wild type protein located to the nucleus. Altogether, our findings validate HORMAD1 as an essential genetic factor in the meiotic process in human. LIMITATIONS, REASONS FOR CAUTION According to one scoring system used to evaluate the clinical validity of male infertility genes, this study would classify HORMAD1 as displaying limited clinical evidence of being involved in male infertility. However, such a score is the maximum possible when only one family is analyzed and the addition of one patient showing a pathogenic or likely pathogenic variant would immediately change this classification to ‘moderate’. Thus, this report should prompt other researchers to screen patients with NOA for this genetic variant. WIDER IMPLICATIONS OF THE FINDINGS Identification of new genetic factors involved in the human meiosis process will contribute to an improvement of our knowledge at the basic level, which in turn will allow the management of better care for infertile patients. Since Hormad1−/− knock-out female mice are also infertile, HORMAD1 could also be involved in human female infertility. Our findings have direct implications for the genetic counseling of patients and their family members. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by Fondation Maladies Rares (High Throughput Sequencing and Rare Diseases—2018, ‘GenOmics of rare diseases’). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER N/A.
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- 2022
4. Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility
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Birgit Stallmeyer, Clara Bühlmann, Rytis Stakaitis, Ann-Kristin Dicke, Farah Ghieh, Luisa Meier, Ansgar Zoch, David MacKenzie MacLeod, Johanna Steingröver, Özlem Okutman, Daniela Fietz, Adrian Pilatz, Antoni Riera-Escamilla, Miguel J. Xavier, Christian Ruckert, Sara Di Persio, Nina Neuhaus, Ali Sami Gurbuz, Ahmet Şalvarci, Nicolas Le May, Kevin McEleny, Corinna Friedrich, Godfried van der Heijden, Margot J. Wyrwoll, Sabine Kliesch, Joris A. Veltman, Csilla Krausz, Stéphane Viville, Donald F. Conrad, Dónal O’Carroll, and Frank Tüttelmann
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Science - Abstract
Abstract piRNAs are crucial for transposon silencing, germ cell maturation, and fertility in male mice. Here, we report on the genetic landscape of piRNA dysfunction in humans and present 39 infertile men carrying biallelic variants in 14 different piRNA pathway genes, including PIWIL1, GTSF1, GPAT2, MAEL, TDRD1, and DDX4. In some affected men, the testicular phenotypes differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal sperm. A reduced number of pachytene piRNAs was detected in the testicular tissue of variant carriers, demonstrating impaired piRNA biogenesis. Furthermore, LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. These results establish the disrupted piRNA pathway as a major cause of human spermatogenic failure and provide insights into transposon silencing in human male germ cells.
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- 2024
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5. Programmed Cell Death 2-Like (Pdcd2l) Is Required for Mouse Embryonic Development
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Richard Burke, Manon S. Oud, Anne E O'Connor, Ozlem Okutman, Daniel M Aguirre, Brendan J Houston, Moira K O'Bryan, Stéphane Viville, Joris A. Veltman, and D. Jo Merriner
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Adult ,Male ,Apoptosis ,Investigations ,QH426-470 ,male infertility ,Male infertility ,Andrology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Pregnancy ,medicine ,Genetics ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,Infertility, Male ,030304 developmental biology ,0303 health sciences ,Gene knockdown ,030219 obstetrics & reproductive medicine ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,sperm function ,Embryo ,biology.organism_classification ,medicine.disease ,Oocyte ,Phenotype ,Spermatozoa ,medicine.anatomical_structure ,Drosophila melanogaster ,embryonic development ,Knockout mouse ,Female ,acrosome ,Carrier Proteins ,pdcd2l ,Germ cell - Abstract
Contains fulltext : 229297.pdf (Publisher’s version ) (Open Access) Globozoospermia is a rare form of male infertility where men produce round-headed sperm that are incapable of fertilizing an oocyte naturally. In a previous study where we undertook a whole exome screen to define novel genetic causes of globozoospermia, we identified homozygous mutations in the gene PDCD2L Two brothers carried a p.(Leu225Val) variant predicted to introduce a novel splice donor site, thus presenting PDCD2L as a potential regulator of male fertility. In this study, we generated a Pdcd2l knockout mouse to test its role in male fertility. Contrary to the phenotype predicted from its testis-enriched expression pattern, Pdcd2l null mice died during embryogenesis. Specifically, we identified that Pdcd2l is essential for post-implantation embryonic development. Pdcd2l(-/-) embryos were resorbed at embryonic days 12.5-17.5 and no knockout pups were born, while adult heterozygous Pdcd2l males had comparable fertility to wildtype males. To specifically investigate the role of PDCD2L in germ cells, we employed Drosophila melanogaster as a model system. Consistent with the mouse data, global knockdown of trus, the fly ortholog of PDCD2L, resulted in lethality in flies at the third instar larval stage. However, germ cell-specific knockdown with two germ cell drivers did not affect male fertility. Collectively, these data suggest that PDCD2L is not essential for male fertility. By contrast, our results demonstrate an evolutionarily conserved role of PDCD2L in development.
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- 2020
6. Aspect génétique de l’infertilité masculine : de la recherche à la clinique
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Stéphane Viville, M. Ben Rhouma, Ozlem Okutman, K. Ben Rhouma, Moncef Benkhalifa, Olfa Tebourbi, Jean Muller, Hatem Bahri, Dynamique des interactions Hôte pathogène, Université de Strasbourg (UNISTRA), Histoire et populations (UR11), Institut national d'études démographiques (INED), and CHU Amiens-Picardie
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0301 basic medicine ,03 medical and health sciences ,030219 obstetrics & reproductive medicine ,030104 developmental biology ,0302 clinical medicine ,Reproductive Medicine ,[SDV]Life Sciences [q-bio] ,Obstetrics and Gynecology ,3. Good health - Abstract
Resume Objectif L’objectif de notre revue est de faire le point sur l’etat actuel de la recherche concernant la genetique de l’infertilite masculine. Nous nous concentrerons sur les anomalies genetiques, qui peuvent conduire a une infertilite masculine non syndromique et les tests genetiques proposes pour les patients. Elle s’adresse principalement aux cliniciens et biologistes de la medecine de la reproduction. Methode Une revue complete de la litterature scientifique disponible sur PubMed a ete realisee en utilisant des mots cles lies a l’infertilite masculine et la genetique. Dans la mesure ou les premiers genes lies a l’infertilite masculine non syndromique ont ete identifies apres les annees 2000, la recherche bibliographique a ete conduite apres cette date. Resultats Trente-trois genes ont ete identifies comme responsables d’une infertilite masculine non syndromique. L’evolution des techniques basees sur l’analyse du genome entier a permis le developpement de methodes plus fructueuses dans l’identification de nouveaux genes et de mutations induisant un phenotype d’infertilite. A travers cet article, nous proposons, par des exemples concrets, une approche clinique pour les tests genetiques en prenant en compte les alterations des analyses spermatiques. Conclusions L’identification et la caracterisation de ces genes et des mutations responsables de certains phenotypes d’infertilite permettent une meilleure prise en charge et un traitement mieux adapte aux patients ainsi qu’une meilleure comprehension des mecanismes physiopathologiques de la gametogenese humaine.
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- 2019
7. Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia
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Liliana Ramos, L A J Hendricks, Lisenka E.L.M. Vissers, Héctor E. Chemes, Moira K O'Bryan, Stéphane Viville, Ozlem Okutman, Manon S. Oud, Joris A. Veltman, P de Vries, and Brendan J Houston
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Male ,Candidate gene ,DNA Copy Number Variations ,Gene mutation ,Biology ,globozoospermia ,male infertility ,Frameshift mutation ,03 medical and health sciences ,symbols.namesake ,genetic diagnosis ,0302 clinical medicine ,consanguinity ,All institutes and research themes of the Radboud University Medical Center ,acrosomal hypoplasia ,Humans ,Exome ,Copy-number variation ,gene mutation ,Globozoospermia ,Exome sequencing ,Infertility, Male ,030304 developmental biology ,Netherlands ,Sanger sequencing ,Genetics ,0303 health sciences ,030219 obstetrics & reproductive medicine ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Rehabilitation ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Australia ,Obstetrics and Gynecology ,Membrane Proteins ,Reproductive Genetics ,teratozoospermia ,ultrastructure ,Spermatozoa ,3. Good health ,Reproductive Medicine ,symbols ,Original Article ,acrosome ,exome sequencing - Abstract
STUDY QUESTION Can exome sequencing identify new genetic causes of globozoospermia? SUMMARY ANSWER Exome sequencing in 15 cases of unexplained globozoospermia revealed deleterious mutations in seven new genes, of which two have been validated as causing globozoospermia when knocked out in mouse models. WHAT IS KNOWN ALREADY Globozoospermia is a rare form of male infertility characterised by round-headed sperm and malformation of the acrosome. Although pathogenic variants in DPY19L2 and SPATA16 are known causes of globozoospermia and explain up to 70% of all cases, genetic causality remains unexplained in the remaining patients. STUDY DESIGN, SIZE, DURATION After pre-screening 16 men for mutations in known globozoospermia genes DPY19L2 and SPATA16, exome sequencing was performed in 15 males with globozoospermia or acrosomal hypoplasia of unknown aetiology. PARTICIPANTS/MATERIALS, SETTING, METHOD Targeted next-generation sequencing and Sanger sequencing was performed for all 16 patients to screen for single-nucleotide variants and copy number variations in DPY19L2 and SPATA16. After exclusion of one patient with DPY19L2 mutations, we performed exome sequencing for the 15 remaining subjects. We prioritised recessive and X-linked protein-altering variants with an allele frequency of MAIN RESULTS AND ROLE OF CHANCE After prioritisation and validation, we identified possibly causative variants in eight of 15 patients investigated by exome sequencing. The analysis revealed homozygous nonsense mutations in ZPBP and CCDC62 in two unrelated patients, as well as rare missense mutations in C2CD6 (also known as ALS2CR11), CCIN, C7orf61 and DHNA17 and a frameshift mutation in GGN in six other patients. All variants identified through exome sequencing, except for the variants in DNAH17, were located in a region of homozygosity. Familial segregation of the nonsense variant in ZPBP revealed two fertile brothers and the patient’s mother to be heterozygous carriers. Paternal DNA was unavailable. Immunohistochemistry confirmed that ZPBP localises to the acrosome in human spermatozoa. Ultrastructural analysis of spermatozoa in the patient with the C7orf61 mutation revealed a mixture of round heads with no acrosomes (globozoospermia) and ovoid or irregular heads with small acrosomes frequently detached from the sperm head (acrosomal hypoplasia). LIMITATIONS, REASONS FOR CAUTION Stringent filtering criteria were used in the exome data analysis which could result in possible pathogenic variants remaining undetected. Additionally, functional follow-up is needed for several candidate genes to confirm the impact of these mutations on normal spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS Our study revealed an important role for mutations in ZPBP and CCDC62 in human globozoospermia as well as five new candidate genes. These findings provide a more comprehensive understanding of the genetics of male infertility and bring us closer to a complete molecular diagnosis for globozoospermia patients which would help to predict the success of reproductive treatments. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by The Netherlands Organisation for Scientific Research (918–15-667); National Health and Medical Research Council of Australia (APP1120356) and the National Council for Scientific Research (CONICET), Argentina, PIP grant 11220120100279CO. The authors have nothing to disclose.
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- 2020
8. A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family
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Moncef Benkhalifa, Stéphane Viville, Sabine Kliesch, Nicolas Charlet-Berguerand, Munevver Serdarogullari, Angeline Gaucherot, Isabelle Aknin, Ozlem Okutman, Frank Tüttelmann, Viviana Herbepin, Mustafa Bahceci, Meral Gultomruk, Ellen Goossens, Jean Marie Garnier, Valérie Lamour, Yoni Baert, Jean Muller, Emre Bakircioglu, Valerie Skory, Marius Teletin, Albrecht Röpke, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dynamique des interactions Hôte pathogène, Université de Strasbourg (UNISTRA), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Vrije Universiteit Brussel (VUB), Sisli Florence Nightingale Hospital [Istanbul, Turkey], University of Münster, CHU de Saint-Étienne Hôpital Nord (Saint Etienne), Université de Picardie Jules Verne (UPJV), Nouvel Hôpital Civil de Strasbourg, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHARLET BERGUERAND, NICOLAS, Biology of the Testis, Basic (bio-) Medical Sciences, Faculty of Medicine and Pharmacy, and Surgical clinical sciences
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Male ,RNA, Messenger/genetics ,0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Aucun ,Whole Exome Sequencing ,Sciences du Vivant [q-bio]/Génétique ,Male infertility ,Consanguinity ,0302 clinical medicine ,Gene Frequency ,Neoplasm Proteins/genetics ,Genes, X-Linked ,genetics ,Exome ,ComputingMilieux_MISCELLANEOUS ,Genetics (clinical) ,Exome sequencing ,Azoospermia ,Genetics ,Sanger sequencing ,030219 obstetrics & reproductive medicine ,Homozygote ,Obstetrics and Gynecology ,General Medicine ,Neoplasm Proteins ,Pedigree ,[SDV] Life Sciences [q-bio] ,Antigens, Neoplasm/genetics ,Sciences du Vivant [q-bio]/Biologie de la reproduction ,Mutation (genetic algorithm) ,symbols ,Azoospermia/genetics ,Adult ,Child, preschool ,Sciences du Vivant [q-bio]/Médecine humaine et pathologie ,Biology ,Polymorphism, Single Nucleotide ,Infertility, Male/genetics ,03 medical and health sciences ,symbols.namesake ,Antigens, Neoplasm ,Exome Sequencing ,medicine ,Humans ,RNA, Messenger ,Gene ,Infertility, Male ,Oligospermia/genetics ,pathology ,Oligospermia ,medicine.disease ,Genes, X-Linked/genetics ,030104 developmental biology ,Reproductive Medicine ,mutation ,Developmental Biology - Abstract
PURPOSE: The purpose of this study was to identify mutations that cause non-syndromic male infertility using whole exome sequencing of family cases. METHODS: We recruited a consanguineous Turkish family comprising nine siblings with male triplets; two of the triplets were infertile as well as one younger infertile brother. Whole exome sequencing (WES) performed on two azoospermic brothers identified a mutation in the melanoma antigen family B4 (MAGEB4) gene which was confirmed via Sanger sequencing and then screened for on control groups and unrelated infertile subjects. The effect of the mutation on messenger RNA (mRNA) and protein levels was tested after in vitro cell transfection. Structural features of MAGEB4 were predicted throughout the conserved MAGE domain. RESULTS: The novel single-base substitution (c.1041A>T) in the X-linked MAGEB4 gene was identified as a no-stop mutation. The mutation is predicted to add 24 amino acids to the C-terminus of MAGEB4. Our functional studies were unable to detect any effect either on mRNA stability, intracellular localization of the protein, or the ability to homodimerize/heterodimerize with other MAGE proteins. We thus hypothesize that these additional amino acids may affect the proper protein interactions with MAGEB4 partners. CONCLUSION: The whole exome analysis of a consanguineous Turkish family revealed MAGEB4 as a possible new X-linked cause of inherited male infertility. This study provides the first clue to the physiological function of a MAGE protein. journal article 2017 May 2017 04 11 imported
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- 2017
9. A new mutation identified in SPATA16 in two globozoospermic patients
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Samira Ibala-Romdhane, Ozlem Okutman, Stéphane Viville, Pierre F. Ray, Elias ElInati, Houda Ghédir, Sylvianne Hennebicq, Camille Fossard, and Ali Saad
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Male ,0301 basic medicine ,Candidate gene ,Genotype ,DNA Mutational Analysis ,Vesicular Transport Proteins ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Teratozoospermia ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Genetic linkage ,Genetics ,medicine ,Humans ,Gene ,Genetics (clinical) ,Sequence Deletion ,Homeodomain Proteins ,Mutation ,030219 obstetrics & reproductive medicine ,Haplotype ,Obstetrics and Gynecology ,General Medicine ,Founder Effect ,030104 developmental biology ,Haplotypes ,Reproductive Medicine ,Developmental Biology ,Founder effect - Abstract
The aim of this study is to identify potential genes involved in human globozoopsermia. Nineteen globozoospermic patients (previously screened for DPY19L2 mutations with no causative mutation) were recruited in this study and screened for mutations in genes implicated in human globozoospermia SPATA16 and PICK1. Using the candidate gene approach and the determination of Spata16 partners by Glutathione S-transferase (GST) pull-down four genes were also selected and screened for mutations. We identified a novel mutation of SPATA16: deletion of 22.6 Kb encompassing the first coding exon in two unrelated Tunisian patients who presented the same deletion breakpoints. The two patients shared the same haplotype, suggesting a possible ancestral founder effect for this new deletion. Four genes were selected using the candidate gene approach and the GST pull-down (GOPC, PICK1, AGFG1 and IRGC) and were screened for mutation, but no variation was identified. The present study confirms the pathogenicity of the SPATA16 mutations. The fact that no variation was detected in the coding sequence of AFGF1, GOPC, PICK1 and IRGC does not mean that they are not involved in human globozoospermia. A larger globozoospermic cohort must be studied in order to accelerate the process of identifying new genes involved in such phenotypes. Until sufficient numbers of patients have been screened, AFGF1, GOPC, PICK1 and IRGC should still be considered as candidate genes.
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- 2016
10. Homozygous Splice Site Mutation in ZP1 Causes Familial Oocyte Maturation Defect
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Umut Büyük, Firat Tulek, Nicolas Charlet-Berguerand, Cem Demirel, Véronique Pfister, Jean Muller, Stéphane Viville, Ozlem Okutman, and Université de Strasbourg (UNISTRA)
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Adult ,Male ,0301 basic medicine ,Zona pellucida glycoprotein ,lcsh:QH426-470 ,female infertility ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,oocyte maturation defect ,Controlled ovarian hyperstimulation ,Biology ,Zona Pellucida Glycoproteins ,Article ,Frameshift mutation ,Andrology ,03 medical and health sciences ,Exon ,Oogenesis ,0302 clinical medicine ,Ovulation Induction ,immature oocytes ,Genetics ,medicine ,Humans ,Genetics (clinical) ,030219 obstetrics & reproductive medicine ,Splice site mutation ,In vitro fertilisation ,Oocyte ,In Vitro Oocyte Maturation Techniques ,Pedigree ,lcsh:Genetics ,030104 developmental biology ,medicine.anatomical_structure ,Mutation ,Oocytes ,Female ,RNA Splice Sites ,Minigene - Abstract
In vitro fertilization (IVF) involves controlled ovarian hyperstimulation using hormones to produce large numbers of oocytes. The success of IVF is tightly linked to the availability of mature oocytes. In most cases, about 70% to 80% of the oocytes are mature at the time of retrieval, however, in rare instances, all of them may be immature, implying that they were not able to reach the metaphase II (MII) stage. The failure to obtain any mature oocytes, despite a well conducted ovarian stimulation in repeated cycles is a very rare cause of primary female infertility, for which the underlying suspected genetic factors are still largely unknown. In this study, we present the whole exome sequencing analysis of a consanguineous Turkish family comprising three sisters with a recurrent oocyte maturation defect. Analysis of the data reveals a homozygous splice site mutation (c.1775-3C>, A) in the zona pellucida glycoprotein 1 (ZP1) gene. Minigene experiments show that the mutation causes the retention of the intron 11 sequence between exon 11 and exon 12, resulting in a frameshift and the likely production of a truncated protein.
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- 2020
11. Genetic evaluation of patients with non-syndromic male infertility
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Moncef Benkhalifa, Ozlem Okutman, Maroua Ben Rhouma, Jean Muller, Stéphane Viville, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, and Nouvel Hôpital Civil de Strasbourg
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0301 basic medicine ,Infertility ,Male ,[SDV]Life Sciences [q-bio] ,media_common.quotation_subject ,Fertility ,Review ,Bioinformatics ,Male infertility ,03 medical and health sciences ,0302 clinical medicine ,Gene panel ,Genetics ,medicine ,Humans ,Spermatogenesis ,ComputingMilieux_MISCELLANEOUS ,Genetics (clinical) ,Selection (genetic algorithm) ,Infertility, Male ,media_common ,Chromosome Aberrations ,030219 obstetrics & reproductive medicine ,business.industry ,Obstetrics and Gynecology ,General Medicine ,medicine.disease ,Testicular sperm extraction ,030104 developmental biology ,Reproductive Medicine ,Evaluation Studies as Topic ,Identification (biology) ,business ,Non syndromic ,Developmental Biology - Abstract
PURPOSE: This review provides an update on the genetics of male infertility with emphasis on the current state of research, the genetic disorders that can lead to non-syndromic male infertility, and the genetic tests available for patients. METHODS: A comprehensive review of the scientific literature referenced in PubMed was conducted using keywords related to male infertility and genetics. The search included articles with English abstracts appearing online after 2000. RESULTS: Mutations in 31 distinct genes have been identified as a cause of non-syndromic human male infertility, and the number is increasing constantly. Screening gene panels by high-throughput sequencing can be offered to patients in order to identify genes involved in various forms of human non-syndromic infertility. We propose a workflow for genetic tests which takes into account semen alterations. CONCLUSIONS: The identification and characterization of the genetic basis of male infertility have broad implications not only for understanding the cause of infertility but also in determining the prognosis, selection of treatment options, and management of couples. Genetic diagnosis is essential for the success of ART techniques and for preserving future fertility as well as the prognosis for testicular sperm extraction (TESE) and adopted therapeutics.
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- 2018
12. Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia
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Jayne Y. Hehir-Kwa, Manon S. Oud, Stéphane Viville, Moira K O'Bryan, Lisenka E.L.M. Vissers, A.M. Meijerink, Joris A. Veltman, Maartje van de Vorst, Petra de Vries, Michiel J Noordam, Kathrin Fleischer, Liliana Ramos, Dorien Lugtenberg, Alexander Hoischen, Dominique Smeets, Ozlem Okutman, Robert I McLachlan, Christian Gilissen, RS: GROW - R4 - Reproductive and Perinatal Medicine, and Klinische Genetica
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0301 basic medicine ,Male ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,VAS-DEFERENS ,Bioinformatics ,Cystic fibrosis ,Severity of Illness Index ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Male infertility ,0302 clinical medicine ,Copy-number variation ,Oligozoospermia ,smMIPs ,HUMAN Y-CHROMOSOME ,CFTR ,Diagnostics ,Genetics (clinical) ,Sex Chromosome Aberrations ,Azoospermia ,Targeted Sequencing ,030219 obstetrics & reproductive medicine ,Sperm Count ,Reproduction ,High-Throughput Nucleotide Sequencing ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] ,Phenotype ,MOLECULAR INVERSION PROBES ,CBAVD ,medicine.medical_specialty ,DNA Copy Number Variations ,MEIOTIC ARREST ,Biology ,Y chromosome ,DPY19L2 DELETION ,HIGH-THROUGHPUT ,Frameshift mutation ,03 medical and health sciences ,Internal medicine ,Genetic variation ,Genetics ,medicine ,Humans ,Male Infertility ,Genetic Predisposition to Disease ,CONGENITAL BILATERAL ABSENCE ,Genetic Testing ,Genetic Association Studies ,Chromosome Aberrations ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,CYSTIC-FIBROSIS ,MUTATIONS ,MALE-INFERTILITY ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Computational Biology ,Reproducibility of Results ,Oligospermia ,medicine.disease ,030104 developmental biology ,Endocrinology ,Mutation ,Klinefelter syndrome - Abstract
Contains fulltext : 182413.pdf (Publisher’s version ) (Closed access) Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY), and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here, we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified five patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11-17 patients (1%-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared with currently used methods.
- Published
- 2017
13. Identification of a new DPY19L2 mutation and a better definition of DPY19L2 deletion breakpoints leading to globozoospermia
- Author
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Géraldine Viot, Houda Ghédir, Stéphane Viville, Ozlem Okutman, Samira Ibala-Romdhane, and Ali Saad
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0301 basic medicine ,Male ,Embryology ,Tunisia ,Chromosome Breakpoints ,Non-allelic homologous recombination ,Gene Dosage ,Vesicular Transport Proteins ,Single-nucleotide polymorphism ,Consanguinity ,Biology ,urologic and male genital diseases ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Genetics ,Humans ,Point Mutation ,Allele ,Molecular Biology ,Alleles ,Infertility, Male ,Homeodomain Proteins ,030219 obstetrics & reproductive medicine ,Point mutation ,Haplotype ,Obstetrics and Gynecology ,Membrane Proteins ,Nuclear Proteins ,Cell Biology ,Exons ,Spermatozoa ,030104 developmental biology ,Reproductive Medicine ,Haplotypes ,RNA Splice Sites ,Carrier Proteins ,Acrosome ,Sequence Alignment ,Gene Deletion ,Developmental Biology - Abstract
STUDY HYPOTHESIS The purpose of this study was to analyze DPY19L2 sequence variants to investigate the mechanism leading to the entire DPY19L2 deletion in a large cohort of infertile globozoospermic patients. STUDY FINDING An improved analysis of the DPY19L2 deletion breakpoints (BPs) allowed us to identify two BPs located in a small 1 kb region and to more precisely localize the BPs reported previously. WHAT IS KNOWN ALREADY Three genes [spermatogenesis associated 16 (SPATA16), protein interacting with PRKCA (PICK1) and DPY19L2] were previously correlated with globozoospermia, but a homozygous deletion of the entire DPY19L2 was identified as the most frequent alteration causing this phenotype. In addition, several point mutations in this gene were reported. In previous work, we have identified nine BPs for the DPY19L2 deletion clustered in two hotspot regions, while others reported a total of five BPs. STUDY DESIGN, SAMPLES/MATERIALS, METHODS We screened for the DPY19L2 deletion and for mutations in the DPY19L2, SPATA16 and PICK1 genes in a cohort of 21 Tunisian globozoospermic patients. In order to characterize the DPY19L2 deletion BPs, we sequenced a 2 kb fragment on low copy repeat (LCR) 1 and LCR2 in Tunisian fertile controls to distinguish between single-nucleotide polymorphisms (SNPs) and LCR-specific markers. MAIN RESULTS AND THE ROLE OF CHANCE Molecular analyses performed on 18 genetically independent individuals showed that 11 (61.1%) were homozygous for the DPY19L2 deletion, 2 (11.1%) were homozygous for the non-synonymous mutation (p.R298C) in exon 8, 1 patient (5.6%) was homozygous for a new splice-site mutation at the junction exon-intron 16 [c.1579_1580+4delAGGTAAinsTCAT] and no DPY19L2, SPATA16 or PICK1 mutations were identified for 4 patients (22.2%). By defining 15 specific LCR markers, we characterized 2 BPs for the DPY19L2 deletion in 11 patients showing the homozygous deletion. Using 20 non-LCR-specific SNPs, we identified 8 distinct haplotypes. LIMITATIONS, REASONS FOR CAUTION A limitation of this study is the small number of patients owing to the rarity of this form of male infertility. WIDER IMPLICATIONS OF THE FINDINGS Our data showed that some nucleotides, described by others as LCR-specific markers and used to limit their BPs, were in fact SNPs demonstrating the difficulty in precisely determining the localization of BPs. LARGE SCALE DATA Not applicable. STUDY FUNDING AND COMPETING INTERESTS This work was supported by the French Centre National de la Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (INSERM), the Ministere de l'Education Nationale et de l'Enseignement Superieur et de la Recherche, the University of Strasbourg, the University Hospital of Strasbourg, the Agence Nationale pour la Recherche, the Agence de la BioMedecine and l'Agence Universitaire de la Francophonie (AUF). There are no conflicts of interest to declare.
- Published
- 2015
14. Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family
- Author
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Ozlem Okutman, Ellen Goossens, Munevver Serdarogullari, Stéphane Viville, Emre Bakircioglu, Moncef Benkhalifa, Valerie Skory, Marius Teletin, Jean Muller, Amélie Piton, Meral Gultomruk, Yoni Baert, Charlotte André Rombaut, Mustafa Bahceci, Basic (bio-) Medical Sciences, Faculty of Medicine and Pharmacy, and Biology of the Testis
- Subjects
Infertility ,Male ,Time Factors ,Turkey ,Translational termination ,Nonsense mutation ,Cell Cycle Proteins ,Consanguinity ,Biology ,White People ,Exon ,Testis ,Genetics ,medicine ,Humans ,Exome ,Genetic Predisposition to Disease ,Spermatogenesis ,Molecular Biology ,Genetics (clinical) ,Exome sequencing ,Infertility, Male ,General Medicine ,Oligospermia ,Organ Size ,Sequence Analysis, DNA ,medicine.disease ,Pedigree ,Meiosis ,Codon, Nonsense - Abstract
Infertility is a global healthcare problem, and despite long years of assisted reproductive activities, a significant number of cases remain idiopathic. Our currently restricted understanding of basic mechanisms driving human gametogenesis severely limits the improvement of clinical care for infertile patients. Using exome sequencing, we identified a nonsense mutation leading to a premature stop in the TEX15 locus (c.2130T>G, p.Y710*) in a consanguineous Turkish family comprising eight siblings in which three brothers were identified as infertile. TEX15 displays testis-specific expression, maps to chromosome 8, contains four exons and encodes a 2789-amino acid protein with uncertain function. The mutation, which should lead to early translational termination at the first exon of TEX15, co-segregated with the infertility phenotype, and our data strongly suggest that it is the cause of spermatogenic defects in the family. All three affected brothers presented a phenotype reminiscent of the one observed in KO mice. Indeed, previously reported results demonstrated that disruption of the orthologous gene in mice caused a drastic reduction in testis size and meiotic arrest in the first wave of spermatogenesis in males while female KO mice were fertile. The data from our study of one Turkish family suggested that the identified mutation correlates with a decrease in sperm count over time. A diagnostic test identifying the mutation in man could provide an indication of spermatogenic failure and prompt patients to undertake sperm cryopreservation at an early age.
- Published
- 2015
15. Achondroplasia in Turkey is defined by recurrent G380R mutation of the FGFR3 gene
- Author
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Sacide, Pehlivan, Ferda, Ozkinay, Ozlem, Okutman, Ozgür, Coğulu, Ali, Ozcan, Tufan, Cankaya, and Ayfer, Ulgenalp
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Adult ,Adolescent ,Turkey ,Child, Preschool ,DNA Mutational Analysis ,Mutation ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Protein-Tyrosine Kinases ,Child ,Receptors, Fibroblast Growth Factor ,Achondroplasia - Abstract
Achondroplasia, the most common form of skeletal dysplasia in man, has autosomal dominant inheritance and causes severe dwarfism. More than 90% of patients with achondroplasia have a G to A transversion or G to C transversion at position 1138 of the fibroblast growth factor receptor-3 (FGFR3) gene resulting in the substitution of an arginine for a glycine residue at position 380 (G380R) of the FGFR3 protein. In this study, 12 unrelated Turkish patients with achondroplasia were evaluated for the G to A and G to C transversion at position 1138 of the FGFR3 gene. Eleven of 12 patients carried the G to A mutation heterozygously. None of the patients had the G to C mutation at the same position. In conclusion, the vast majority of Turkish achondroplasia patients have the same mutation that has been most often defined in patients with achondroplasia from other countries. Our results give further support to the fact that the G380R mutation of FGFR-3 is the most common mutation causing achondroplasia in different populations.
- Published
- 2003
16. Homozygous Splice Site Mutation in ZP1 Causes Familial Oocyte Maturation Defect
- Author
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Özlem Okutman, Cem Demirel, Firat Tülek, Veronique Pfister, Umut Büyük, Jean Muller, Nicolas Charlet-Berguerand, and Stéphane Viville
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immature oocytes ,oocyte maturation defect ,female infertility ,Genetics ,QH426-470 - Abstract
In vitro fertilization (IVF) involves controlled ovarian hyperstimulation using hormones to produce large numbers of oocytes. The success of IVF is tightly linked to the availability of mature oocytes. In most cases, about 70% to 80% of the oocytes are mature at the time of retrieval, however, in rare instances, all of them may be immature, implying that they were not able to reach the metaphase II (MII) stage. The failure to obtain any mature oocytes, despite a well conducted ovarian stimulation in repeated cycles is a very rare cause of primary female infertility, for which the underlying suspected genetic factors are still largely unknown. In this study, we present the whole exome sequencing analysis of a consanguineous Turkish family comprising three sisters with a recurrent oocyte maturation defect. Analysis of the data reveals a homozygous splice site mutation (c.1775-3C>A) in the zona pellucida glycoprotein 1 (ZP1) gene. Minigene experiments show that the mutation causes the retention of the intron 11 sequence between exon 11 and exon 12, resulting in a frameshift and the likely production of a truncated protein.
- Published
- 2020
- Full Text
- View/download PDF
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