101 results on '"Ledig, S."'
Search Results
2. Mutations in WNT9B are associated with Mayer–Rokitansky–Küster–Hauser syndrome
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Waschk, D. E.J., Tewes, A.-C., Römer, T., Hucke, J., Kapczuk, K., Schippert, C., Hillemanns, P., Wieacker, P., and Ledig, S.
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- 2016
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3. Genetische Ursachen der prämaturen Ovarialinsuffizienz und Ovardysgenesie
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Ledig, S. and Wieacker, P.
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- 2011
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4. Hypogonadotroper Hypogonadismus aufgrund eines IHH oder Kallmann-Syndroms beim Mann
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Behre, H.M., Tüttelmann, F., Ledig, S., and Wieacker, P.
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- 2011
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5. Genetisch bedingte Entwicklungsstörungen der Genitalwege
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Wieacker, P., Ledig, S., and Bogdanova, N.
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- 2011
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6. Androgeninsensitivität
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Wieacker, P. and Ledig, S.
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- 2011
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7. Störungen der männlichen Gonadendifferenzierung
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Wieacker, P. and Ledig, S.
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- 2011
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8. Biallelic mutations in M1AP are associated with meiotic arrest, severely impaired spermatogenesis and male infertility
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Friedrich, C., Temel, S.G., Nagirnaja, L., Oud, M.S., Lopes, A.M., van der Heijden, G.W., Heald, J., Rotte, N., Wistuba, J., Wöste, M., Ledig, S., Krenz, H., Smits, R.M., Carvalho, F., Gonçalves, João, Fietz, D., Türkgenç, B., Ergören, M.C., Çetinkaya, M., Başar, M., Kahraman, S., McEleny, K., Xavier, M.J., Turner, H., Pilatz, A., Röpke, A., Dugas, M., Kliesch, S., Neuhaus, N., GEMINI Consortium, Aston, K.I., Conrad, D.F., Veltman, J.A., Wyrwoll, M.J., and Tüttelmann, F.
- Subjects
Male Infertility ,M1AP ,Azoospermia ,Doenças Genéticas - Abstract
Male infertility affects ~7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis, but so far only few validated causal genes have been reported. To address this gap, we performed whole exome sequencing in 58 men with unexplained meiotic arrest and identified in three unrelated men the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 arresting protein. This variant results in a truncated protein lacking 57% of its full-length as shown in vitro by heterologous expression of mutated M1AP. Next, we screened four large cohorts of 1904 infertile men from the International Male Infertility Genomics Consortium (IMIGC) and identified three additional cases carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant p.(Pro389Leu) segregated with infertility in five men from a consanguineous Turkish family (LOD score = 3.28). The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype was described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP cause autosomal recessive severe spermatogenic failure and male infertility. In view of the evidences from several independent groups and populations, M1AP should be included in the growing list of validated male infertility genes. This work was supported by DFG Clinical Research Unit “Male Germ Cells: from Genes to Function” (CRU326). info:eu-repo/semantics/publishedVersion
- Published
- 2020
9. Frame shift mutation of LHX1 is associated with Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome
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Ledig, S., Brucker, S., Barresi, G., Schomburg, J., Rall, K., and Wieacker, P.
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- 2012
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10. Array-CGH analysis in patients with syndromic and non-syndromic XY gonadal dysgenesis: evaluation of array CGH as diagnostic tool and search for new candidate loci
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Ledig, S., Hiort, O., Scherer, G., Hoffmann, M., Wolff, G., Morlot, S., Kuechler, A., and Wieacker, P.
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- 2010
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11. Significance of the Caspase Family in Helicobacter pylori Induced Gastric Epithelial Apoptosis
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Potthoff, A., Ledig, S., Martin, J., Jandl, O., Cornberg, M., Obst, B., Beil, W., Manns, M. P., and Wagner, S.
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- 2002
12. New Technologies for the identification of novel markers of Disorders of Sex Development
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Bashamboo, A., Ledig, S., Wieacker, P., Achermann, J.C., and McElreavey, K.
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- 2010
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13. Mutations inWNT9Bare associated with Mayer-Rokitansky-Küster-Hauser syndrome
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Waschk, D.E.J., primary, Tewes, A.-C., additional, Römer, T., additional, Hucke, J., additional, Kapczuk, K., additional, Schippert, C., additional, Hillemanns, P., additional, Wieacker, P., additional, and Ledig, S., additional
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- 2016
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14. Sex. Dev
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Jakubiczka, S., Schröder, C., Ullmann, R., Volleth, M., Ledig, S., Gilberg, E., Kroisel, P., and P. Wieacker, P.
- Abstract
Campomelic dysplasia (MIM 114290) is a severe malformation syndrome frequently accompanied by male-to-female sex reversal. Causative are mutations within the SOX9 gene on 17q24.3 as well as chromosomal aberrations (translocations, inversions or deletions) in the vicinity of SOX9 . Here, we report on a patient with muscular hypotonia, craniofacial dysmorphism, cleft palate, brachydactyly, malformations of thoracic spine, and gonadal dysgenesis with female external genitalia and müllerian duct derivatives in the presence of a male karyotype. X-ray examination and clinical examinations revealed no signs of campomelia. The combination of molecular cytogenetic analysis and array CGH revealed an unbalanced translocation between one chromosome 7 and one chromosome 17 [46,XY,t(7; 17)(q33;q24).ish t(7; 17) (wcp7+,wcp17+;wcp7+wcp17+)] with a deletion of approximately 4.2 Mb located about 0.5 Mb upstream of SOX9 . STS analysis confirmed the deletion of chromosome 17, which has occurred de novo on the paternal chromosome. The proximal breakpoint on chromosome 17 is localized outside the known breakpoint cluster regions. The deletion on chromosome 17q24 removes several genes. Among these genes PRKAR1A is deleted. Inactivating mutations of PRKAR1A cause Carney complex. To our knowledge, this is the first report of a patient with acampomelic campomelic dysplasia, carrying both a deletion and a translocation.
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- 2010
15. Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development
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Ledig, S., primary, Hiort, O., additional, Wunsch, L., additional, and Wieacker, P., additional
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- 2012
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16. Translocation and Deletion around SOX9 in a Patient with Acampomelic Campomelic Dysplasia and Sex Reversal
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Jakubiczka, S., primary, Schröder, C., additional, Ullmann, R., additional, Volleth, M., additional, Ledig, S., additional, Gilberg, E., additional, Kroisel, P., additional, and Wieacker, P., additional
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- 2010
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17. Copy Number Variants in Premature Ovarian Failure and Ovarian Dysgenesis
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Ledig, S., primary, Röpke, A., additional, and Wieacker, P., additional
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- 2010
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18. New Technologies for the Identification of Novel Genetic Markers of Disorders of Sex Development (DSD)
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Bashamboo, A., primary, Ledig, S., additional, Wieacker, P., additional, Achermann, J.C., additional, and McElreavey, K., additional
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- 2010
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19. Gekoppelte Simulation äußerer und innerer Transportprozesse bei der konvektiven Trocknung poröser Körper
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Ledig, S. F., primary, Militzer, K.-E., additional, and Mollekopf, N., additional
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- 2005
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20. Role of the Receptor-Mediated Apoptosis in Helicobacter pylori in Gastric Epithelial Cells
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Ledig, S., primary, Wagner, S., additional, Manns, M.P., additional, Beil, W., additional, and Athmann, C., additional
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- 2004
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21. AIRFLOW DISTRIBUTIONS IN THE FILLET SPACES OF A TIMBER STACK
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Ledig, S., primary, Nijdam, J., additional, and Keey, R., additional
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- 2001
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22. MEASURED GAS VELOCITY AND MOISTURE CONTENT DISTRIBUTION IN A CONVECTIVE VACUUM KILN
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Ledig, S. F., primary and Militzer, K.-E., additional
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- 2000
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23. Characterization of effluent from direct and indirect steaming of beech timber
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Ledig, S. F., Slavik, I., Broege, M., and Mollekopf, N.
- Abstract
Condensate samples were collected from industrial kilns with direct and indirect steaming systems. Their composition was analyzed to determine the concentration of organic components as well as COD and BOD parameters. The main classes of organic compounds of the condensate samples were saccharides, organic acids, aldehydes, and phenols. Due to the measured COD and BOD values a treatment prior to discharge was indicated. Both aerobic and anaerobic biological treatment tests exhibited high elimination rates of the organic components.
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- 2004
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24. Biallelic mutations in M1AP are associated with meiotic arrest, severely impaired spermatogenesis and male infertility
- Author
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Friedrich, C., Temel, S. G., Nagirnaja, L., Oud, M. S., Lopes, A. M., Heijden, G. W., Heald, J., Rotte, N., Wistuba, J., Woeste, M., Ledig, S., Krenz, H., Smits, R. M., Carvalho, F., Goncalves, J., Fietz, D., Turkgenc, B., Mahmut Cerkez Ergoren, Cetinkaya, M., Basar, M., Kahraman, S., Mceleny, K., Xavier, M. J., Turner, H., Pilatz, A., Roepke, A., Dugas, M., Kliesch, S., Neuhaus, N., Aston, K. I., Conrad, D. F., Veltman, J. A., Wyrwoll, M. J., and Tuettelmann, F.
25. The role of BCL-2 and FADD in Helicobacter pylori induced apoptosis of human gastric epithelial cells
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Ledig, S., Sobek-Klocke, I., Kubicka, S., Beil, W., Martin, I., Kirchner, G.I., Manns, M.P., Obst, B., and Wagner, S.
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- 2001
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26. Effect of H. pylori on the expression of TRAIL receptor subtypes and apoptosis in human gastric epithelial cells
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Martin, J.H., Potthoff, A., Comberg, M., Sobek-Klocke, I., Ledig, S., Jandl, O., Beil, W., Mundt, B., Manns, M.P., Goeke, M., Gebhardt, T., and Wagner, S.
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- 2001
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27. Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer.
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Rhiem K, Zachariae S, Waha A, Grill S, Hester A, Golatta M, van Mackelenbergh M, Fehm T, Schlaiß T, Ripperger T, Ledig S, Meisel C, Speiser D, Veselinovic K, Schröder C, Witzel I, Gallwas J, Weber BHF, Solbach C, Aktas B, Hahnen E, Engel C, and Schmutzler R
- Abstract
Introduction: International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis., Patients and Methods: In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19-78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression., Results: 260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes ( BRCA1 : n = 170 [10.6%]; BRCA2 : n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years ( n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21-1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years., Conclusion: Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed., Competing Interests: Christopher Schröder reports an institutional grant from Illumina and research grants from BMS Stiftung Immunonkologie outside the submitted work. Julia Gallwas is a member of the academic advisory board of the Bundesaerztekammer and was paid for lectures for Merck Sharp & Dohme and Roche Diagnostics between 2017 and 2019. All other authors have no conflicts to declare., (Copyright © 2023 by The Author(s). Published by S. Karger AG, Basel.)
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- 2023
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28. Genetic Architecture of Azoospermia-Time to Advance the Standard of Care.
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Wyrwoll MJ, Köckerling N, Vockel M, Dicke AK, Rotte N, Pohl E, Emich J, Wöste M, Ruckert C, Wabschke R, Seggewiss J, Ledig S, Tewes AC, Stratis Y, Cremers JF, Wistuba J, Krallmann C, Kliesch S, Röpke A, Stallmeyer B, Friedrich C, and Tüttelmann F
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- Humans, Male, Prospective Studies, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Standard of Care, Testis, Azoospermia genetics, Azoospermia complications, Azoospermia diagnosis, Infertility, Male diagnosis, Infertility, Male genetics
- Abstract
Background: Crypto- and azoospermia (very few/no sperm in the semen) are main contributors to male factor infertility. Genetic causes for spermatogenic failure (SPGF) include Klinefelter syndrome and Y-chromosomal azoospermia factor microdeletions, and CFTR mutations for obstructive azoospermia (OA). However, the majority of cases remain unexplained because monogenic causes are not analysed., Objective: To elucidate the monogenic contribution to azoospermia by prospective exome sequencing and strict application of recent clinical guidelines., Design, Setting, and Participants: Since January 2017, we studied crypto- and azoospermic men without chromosomal aberrations and Y-chromosomal microdeletions attending the Centre of Reproductive Medicine and Andrology, Münster., Outcome Measurements and Statistical Analysis: We performed exome sequencing in 647 men, analysed 60 genes having at least previous limited clinical validity, and strictly assessed variants according to clinical guidelines., Results and Limitations: Overall, 55 patients (8.5%) with diagnostic genetic variants were identified. Of these patients, 20 (3.1%) carried mutations in CFTR or ADGRG2, and were diagnosed with OA. In 35 patients (5.4%) with SPGF, mutations in 20 different genes were identified. According to ClinGen criteria, 19 of the SPGF genes now reach at least moderate clinical validity. As limitations, only one transcript per gene was considered, and the list of genes is increasing rapidly so cannot be exhaustive., Conclusions: The number of diagnostic genes in crypto-/azoospermia was almost doubled to 21 using exome-based analyses and clinical guidelines. Application of this procedure in routine diagnostics will significantly improve the diagnostic yield and clinical workup as the results indicate the success rate of testicular sperm extraction., Patient Summary: When no sperm are found in the semen, a man cannot conceive naturally. The causes are often unknown, but genetics play a major role. We searched for genetic variants in a large group of patients and found causal mutations for one in 12 men; these predict the chances for fatherhood., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
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- 2023
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29. MAP kinase activating death domain deficiency is a novel cause of impaired lymphocyte cytotoxicity.
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Schütze K, Groß M, Cornils K, Wustrau K, Schneppenheim S, Lenhartz H, Korenke GC, Janka G, Ledig S, Müller I, Ehl S, and Lehmberg K
- Subjects
- Female, Humans, Death Domain, Killer Cells, Natural metabolism, T-Lymphocytes, Cytotoxic metabolism, Cytotoxicity, Immunologic, Primary Immunodeficiency Diseases metabolism
- Abstract
Most hereditary forms of hemophagocytic lymphohistiocytosis (HLH) are caused by defects of cytotoxicity, including the vesicle trafficking disorder Griscelli syndrome type 2 (GS2, RAB27A deficiency). Deficiency of the mitogen-activated protein kinase activating death domain protein (MADD) results in a protean syndrome with neurological and endocrinological involvement. MADD acts as a guanine nucleotide exchange factor for small guanosine triphosphatases, including RAB27A. A homozygous splice site mutation in MADD was identified in a female infant with syndromic features, secretory diarrhea, and features of HLH. Aberrant splicing caused by this mutation leads to an in-frame deletion of 30 base pairs and favors other aberrant variants. Patient natural killer (NK) cells and cytotoxic T cells showed a severe degranulation defect leading to absent perforin-mediated cytotoxicity. Platelets displayed defective adenosine triphosphate secretion, similar to that in GS2. To prove causality, we introduced a CRISPR/Cas9-based MADD knockout in the NK cell line NK-92mi. MADD-deficient NK-92mi cells showed a degranulation defect and impaired cytotoxicity similar to that of the patient. The defect of cytotoxicity was confirmed in another patient with MADD deficiency. In conclusion, RAB27A-interacting MADD is involved in vesicle release by cytotoxic cells and platelets. MADD deficiency causes a degranulation defect and represents a novel disease predisposing to an HLH phenotype., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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30. Expanding the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to XX gonadal dysgenesis.
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Altunoglu U, Börklü E, Shukla A, Escande-Beillard N, Ledig S, Azaklı H, Nayak SS, Eraslan S, Girisha KM, Kennerknecht I, and Kayserili H
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- Abnormalities, Multiple genetics, Consanguinity, Disorders of Sex Development diagnosis, Disorders of Sex Development genetics, Facies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Pedigree, Polymorphism, Single Nucleotide, Gonadal Dysgenesis, 46,XX diagnosis, Gonadal Dysgenesis, 46,XX genetics, Gonadal Dysgenesis, 46,XY diagnosis, Gonadal Dysgenesis, 46,XY genetics, Mutation, Phenotype, Protein Phosphatase 2 genetics
- Abstract
Homozygous variants in PPP2R3C have been reported to cause a syndromic 46,XY complete gonadal dysgenesis phenotype with extragonadal manifestations (GDRM, MIM# 618419) in patients from four unrelated families, whereas heterozygous variants have been linked to reduced fertility with teratozoospermia (SPGF36, MIM# 618420) in male carriers. We present eight patients from four unrelated families of Turkish and Indian descent with three different germline homozygous PPP2R3C variants including a novel in-frame duplication (c.639_647dupTTTCTACTC, p.Ser216_Tyr218dup). All patients exhibit recognizable facial dysmorphisms allowing gestalt diagnosis. In two 46,XX patients with hypergonadotropic hypogonadism and nonvisualized gonads, primary amenorrhea along with absence of secondary sexual characteristics and/or unique facial gestalt led to the diagnosis. 46,XY affected individuals displayed a spectrum of external genital phenotypes from ambiguous genitalia to complete female. We expand the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to both XY and XX gonadal dysgenesis. Our findings supported neither ocular nor muscular involvement as major criteria of the syndrome. We also did not encounter infertility problems in the carriers. Since both XX and XY individuals were affected, we hypothesize that PPP2R3C is essential in the early signaling cascades controlling sex determination in humans., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)
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- 2022
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31. Rubella vaccine-induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity.
- Author
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Groß M, Speckmann C, May A, Gajardo-Carrasco T, Wustrau K, Maier SL, Panning M, Huzly D, Agaimy A, Bryceson YT, Choo S, Chow CW, Dückers G, Fasth A, Fraitag S, Gräwe K, Haxelmans S, Holzinger D, Hudowenz O, Hübschen JM, Khurana C, Kienle K, Klifa R, Korn K, Kutzner H, Lämmermann T, Ledig S, Lipsker D, Meeths M, Naumann-Bartsch N, Rascon J, Schänzer A, Seidl M, Tesi B, Vauloup-Fellous C, Vollmer-Kary B, Warnatz K, Wehr C, Neven B, Vargas P, Sepulveda FE, Lehmberg K, Schmitt-Graeff A, and Ehl S
- Subjects
- Child, Child, Preschool, Female, Granuloma genetics, Granuloma immunology, Granuloma virology, Humans, Infant, Phenotype, Rubella genetics, Rubella immunology, Rubella virology, Skin immunology, Skin virology, Granuloma etiology, Rubella Vaccine adverse effects, T-Lymphocytes immunology
- Abstract
Background: Rubella virus-induced granulomas have been described in patients with various inborn errors of immunity. Most defects impair T-cell immunity, suggesting a critical role of T cells in rubella elimination. However, the molecular mechanism of virus control remains elusive., Objective: This study sought to understand the defective effector mechanism allowing rubella vaccine virus persistence in granulomas., Methods: Starting from an index case with Griscelli syndrome type 2 and rubella skin granulomas, this study combined an international survey with a literature search to identify patients with cytotoxicity defects and granuloma. The investigators performed rubella virus immunohistochemistry and PCR and T-cell migration assays., Results: This study identified 21 patients with various genetically confirmed cytotoxicity defects, who presented with skin and visceral granulomas. Rubella virus was demonstrated in all 12 accessible biopsies. Granuloma onset was typically before 2 years of age and lesions persisted from months to years. Granulomas were particularly frequent in MUNC13-4 and RAB27A deficiency, where 50% of patients at risk were affected. Although these proteins have also been implicated in lymphocyte migration, 3-dimensional migration assays revealed no evidence of impaired migration of patient T cells. Notably, patients showed no evidence of reduced control of concomitantly given measles, mumps, or varicella live-attenuated vaccine or severe infections with other viruses., Conclusions: This study identified lymphocyte cytotoxicity as a key effector mechanism for control of rubella vaccine virus, without evidence for its need in control of live measles, mumps, or varicella vaccines. Rubella vaccine-induced granulomas are a novel phenotype with incomplete penetrance of genetic disorders of cytotoxicity., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
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- 2022
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32. Primary haemophagocytic lymphohistiocytosis (Chédiak-Higashi Syndrome) triggered by acute SARS-CoV-2 infection in a six-week-old infant.
- Author
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Lange M, Linden T, Müller HL, Flasskuehler MA, Koester H, Lehmberg K, Ledig S, Ehl S, Heep A, and Beske F
- Subjects
- Acute Disease, COVID-19 physiopathology, Humans, Infant, Newborn, Lymphohistiocytosis, Hemophagocytic physiopathology, Male, SARS-CoV-2 isolation & purification, COVID-19 complications, Lymphohistiocytosis, Hemophagocytic virology
- Published
- 2021
- Full Text
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33. Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility.
- Author
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Wyrwoll MJ, Temel ŞG, Nagirnaja L, Oud MS, Lopes AM, van der Heijden GW, Heald JS, Rotte N, Wistuba J, Wöste M, Ledig S, Krenz H, Smits RM, Carvalho F, Gonçalves J, Fietz D, Türkgenç B, Ergören MC, Çetinkaya M, Başar M, Kahraman S, McEleny K, Xavier MJ, Turner H, Pilatz A, Röpke A, Dugas M, Kliesch S, Neuhaus N, Aston KI, Conrad DF, Veltman JA, Friedrich C, and Tüttelmann F
- Subjects
- Adult, Alleles, Animals, Azoospermia genetics, Homozygote, Humans, Male, Mice, Phenotype, Spermatozoa abnormalities, Testis abnormalities, Turkey, Exome Sequencing methods, Cell Cycle Checkpoints genetics, Infertility, Male genetics, Meiosis genetics, Mutation genetics, Proteins genetics, Spermatogenesis genetics
- Abstract
Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
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34. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.
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Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, Barbieri E, Bartram CR, Blanco A, Blümcke B, Bonache S, Bonanni B, Borg Å, Bortesi B, Brunet J, Bruzzone C, Bucksch K, Cagnoli G, Caldés T, Caliebe A, Caligo MA, Calvello M, Capone GL, Caputo SM, Carnevali I, Carrasco E, Caux-Moncoutier V, Cavalli P, Cini G, Clarke EM, Concolino P, Cops EJ, Cortesi L, Couch FJ, Darder E, de la Hoya M, Dean M, Debatin I, Del Valle J, Delnatte C, Derive N, Diez O, Ditsch N, Domchek SM, Dutrannoy V, Eccles DM, Ehrencrona H, Enders U, Evans DG, Farra C, Faust U, Felbor U, Feroce I, Fine M, Foulkes WD, Galvao HCR, Gambino G, Gehrig A, Gensini F, Gerdes AM, Germani A, Giesecke J, Gismondi V, Gómez C, Gómez Garcia EB, González S, Grau E, Grill S, Gross E, Guerrieri-Gonzaga A, Guillaud-Bataille M, Gutiérrez-Enríquez S, Haaf T, Hackmann K, Hansen TVO, Harris M, Hauke J, Heinrich T, Hellebrand H, Herold KN, Honisch E, Horvath J, Houdayer C, Hübbel V, Iglesias S, Izquierdo A, James PA, Janssen LAM, Jeschke U, Kaulfuß S, Keupp K, Kiechle M, Kölbl A, Krieger S, Kruse TA, Kvist A, Lalloo F, Larsen M, Lattimore VL, Lautrup C, Ledig S, Leinert E, Lewis AL, Lim J, Loeffler M, López-Fernández A, Lucci-Cordisco E, Maass N, Manoukian S, Marabelli M, Matricardi L, Meindl A, Michelli RD, Moghadasi S, Moles-Fernández A, Montagna M, Montalban G, Monteiro AN, Montes E, Mori L, Moserle L, Müller CR, Mundhenke C, Naldi N, Nathanson KL, Navarro M, Nevanlinna H, Nichols CB, Niederacher D, Nielsen HR, Ong KR, Pachter N, Palmero EI, Papi L, Pedersen IS, Peissel B, Perez-Segura P, Pfeifer K, Pineda M, Pohl-Rescigno E, Poplawski NK, Porfirio B, Quante AS, Ramser J, Reis RM, Revillion F, Rhiem K, Riboli B, Ritter J, Rivera D, Rofes P, Rump A, Salinas M, Sánchez de Abajo AM, Schmidt G, Schoenwiese U, Seggewiß J, Solanes A, Steinemann D, Stiller M, Stoppa-Lyonnet D, Sullivan KJ, Susman R, Sutter C, Tavtigian SV, Teo SH, Teulé A, Thomassen M, Tibiletti MG, Tischkowitz M, Tognazzo S, Toland AE, Tornero E, Törngren T, Torres-Esquius S, Toss A, Trainer AH, Tucker KM, van Asperen CJ, van Mackelenbergh MT, Varesco L, Vargas-Parra G, Varon R, Vega A, Velasco Á, Vesper AS, Viel A, Vreeswijk MPG, Wagner SA, Waha A, Walker LC, Walters RJ, Wang-Gohrke S, Weber BHF, Weichert W, Wieland K, Wiesmüller L, Witzel I, Wöckel A, Woodward ER, Zachariae S, Zampiga V, Zeder-Göß C, Lázaro C, De Nicolo A, Radice P, Engel C, Schmutzler RK, Goldgar DE, and Spurdle AB
- Subjects
- Alternative Splicing, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Humans, Likelihood Functions, Male, Multifactorial Inheritance, Neoplasms genetics, BRCA1 Protein genetics, BRCA2 Protein genetics, Computational Biology methods, Mutation, Missense, Neoplasms diagnosis
- Abstract
The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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35. Elaborations on Corallopyronin A as a Novel Treatment Strategy Against Genital Chlamydial Infections.
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Loeper N, Graspeuntner S, Ledig S, Kaufhold I, Hoellen F, Schiefer A, Henrichfreise B, Pfarr K, Hoerauf A, Shima K, and Rupp J
- Abstract
Ascending Chlamydia trachomatis infection causes functional damage to the fallopian tubes, which may lead to ectopic pregnancy and infertility in women. Treatment failures using the standard regimens of doxycycline and azithromycin have been observed. We tested the polyketide-derived α-pyrone antibiotic Corallopyronin A (CorA) that inhibits the bacterial DNA dependent RNA polymerase and has strong activity against various extracellular and some intracellular bacteria. Extensive testing in cell culture infection models and in an ex vivo human fallopian tube model under different oxygen concentrations was performed to assess the anti-chlamydial efficacy of CorA at physiological conditions. CorA showed high efficacy against C. trachomatis (MIC
N/H : 0.5 μg/mL for serovar D and L2), C. muridarum (MICN/H : 0.5 μg/mL), and C. pneumoniae (MICN/H : 1 μg/mL) under normoxic (N) and hypoxic (H) conditions. Recoverable inclusion forming units were significantly lower already at 0.25 μg/mL for all tested chlamydiae. CorA at a concentration of 1 μg/mL was also effective against already established C. trachomatis and C. pneumoniae infections (up to 24 h.p.i.) in epithelial cells, while efficacy against C. muridarum was limited to earlier time points. A preliminary study using a C. muridarum genital infection model revealed corresponding limitations in the efficacy. Importantly, in an ex vivo human fallopian tube model, the growth of C. trachomatis was significantly inhibited by CorA at concentrations of 1-2 μg/mL under normoxic and hypoxic conditions. The overall high efficacies of CorA against C. trachomatis in cell culture and an ex vivo human fallopian tube model under physiological oxygen concentrations qualifies this drug as a candidate that should be further investigated.- Published
- 2019
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36. Sequence Variants in TBX6 Are Associated with Disorders of the Müllerian Ducts: An Update.
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Tewes AC, Hucke J, Römer T, Kapczuk K, Schippert C, Hillemanns P, Wieacker P, and Ledig S
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- Base Sequence, Case-Control Studies, Female, Humans, 46, XX Disorders of Sex Development genetics, Congenital Abnormalities genetics, Genetic Predisposition to Disease, Mullerian Ducts abnormalities, Mullerian Ducts pathology, Mutation genetics, T-Box Domain Proteins genetics
- Abstract
Müllerian anomalies comprise the Mayer-Rokitansky-Küster-Hauser syndrome as well as fusion defects of the müllerian ducts. Recurrent micro-aberrations like deletions in 16p11.2 encompassing TBX6 were found to be causative in these patients. TBX6 encodes a transcription factor which plays a role in paraxial mesoderm differentiation/specification. In previous studies, we and other groups found possibly pathogenic variants in TBX6 in patients with müllerian anomalies. Since we suggested TBX6 as a strong candidate, we performed sequential analysis of the TBX6 gene in additional 125 patients with müllerian anomalies, and 2 possibly pathogenic missense variants and 1 nonsense substitution in TBX6 in 4/125 patients were found. The missense variant c.484G>A, which we have described in a previous study, was reidentified but with no higher frequency as in our controls. We detected 3 possibly pathogenic variants in TBX6 and could show that the variant c.484G>A is not causative for disorders of the müllerian ducts in the non-Finnish European population. In summary, we present increasing evidence for association of variants in TBX6 with malformations of the müllerian ducts., (© 2019 S. Karger AG, Basel.)
- Published
- 2019
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37. Search for altered imprinting marks in Mayer-Rokitansky-Küster-Hauser patients.
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Eggermann T, Ledig S, Begemann M, Elbracht M, Kurth I, and Wieacker P
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- 46, XX Disorders of Sex Development pathology, Adult, Chromosomes, Human, Pair 11 genetics, Congenital Abnormalities pathology, DNA Methylation, Female, Humans, Mullerian Ducts pathology, Silver-Russell Syndrome pathology, 46, XX Disorders of Sex Development genetics, Congenital Abnormalities genetics, Genomic Imprinting, Mullerian Ducts abnormalities, Silver-Russell Syndrome genetics
- Abstract
Background: Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) is the second most common cause of primary amenorrhea and characterized by absence of the uterus and the upper part of the vagina. The etiology of MRKH is mainly unknown but a contribution of genomic alterations is probable. A molecular disturbance so far neglected in MRKH research is aberrant methylation at imprinted loci. In fact, MRKH has been reported in patients with the imprinting disorder Silver-Russell syndrome., Methods: We report on a rare patient with MRKH and SRS due to an ICR1 hypomethylation in 11p15.5. On the basis of this observation we screened a large cohort of MRKH patients (n > 100) for aberrant methylation at nine imprinted loci., Results: We failed to detect any epimutation, thus we conclude that imprinting defects at least at the currently known disease-relevant imprinted loci do not contribute to the isolated MRKH phenotype. However, it cannot be excluded that altered methylation marks at other loci are involved in the etiology of MRKH., Conclusion: The molecular basis for MRKH remains unclear in the majority of patients, but future studies on the association between MRKH and ICR1 hypomethylation/SRS will to enlighten the role of epigenetics in the etiology of MRKH., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Published
- 2018
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38. Effective inhibition of rifampicin-resistant Chlamydia trachomatis by the novel DNA-dependent RNA polymerase inhibitor corallopyronin A.
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Shima K, Ledig S, Loeper N, Schiefer A, Pfarr K, Hoerauf A, Graspeuntner S, and Rupp J
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- Animals, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents pharmacokinetics, Chlamydia trachomatis isolation & purification, Epithelial Cells microbiology, HeLa Cells, Humans, Lactones administration & dosage, Lactones pharmacokinetics, Mice, Microbial Sensitivity Tests, Plasma chemistry, Anti-Bacterial Agents pharmacology, Chlamydia trachomatis drug effects, Chlamydia trachomatis growth & development, DNA-Directed RNA Polymerases antagonists & inhibitors, Drug Resistance, Bacterial, Lactones pharmacology, Rifampin pharmacology
- Published
- 2018
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39. Clinical and genetic aspects of Mayer-Rokitansky-Küster-Hauser syndrome.
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Ledig S and Wieacker P
- Abstract
The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome [MIM 277000] is characterised by the absence of a uterus and vagina in otherwise phenotypically normal women with karyotype 46,XX. Clinically, the MRKH can be subdivided into two subtypes: an isolated or type I form can be delineated from a type II form, which is characterised by extragenital malformations. The so-called Müllerian hypoplasia, renal agenesis, cervicothoracic somite dysplasia (MURCS) association can be seen as the most severe phenotypic outcome. The MRKH syndrome affects at least 1 in 4000 to 5000 female new-borns. Although most of the cases are sporadic, familial clustering has also been described, indicating a genetic cause of the disease. However, the mode of inheritance is autosomal-dominant inheritance with reduced penetrance. High-resolution array-CGH and MLPA analysis revealed recurrent aberrations in different chromosomal regions such as TAR susceptibility locus in 1q21.1, chromosomal regions 16p11.2, and 17q12 and 22q11.21 microduplication and -deletion regions in patients with MRKH. Sequential analysis of the genes LHX1, TBX6 and RBM8A , which are located in chromosomal regions 17q12, 16p11.2 and 1q21.1, yielded in the detection of MRKH-associated mutations. In a subgroup of patients with signs of hyperandrogenaemia mutations of WNT4 have been found to be causative. Analysis of another member of the WNT family, WNT9B , resulted in the detection of some causative mutations in MRKH patients., Competing Interests: Compliance with ethical guidelinesS. Ledig and P. Wieacker declare that they have no competing interests. This article does not contain any studies with human participants or animals performed by any of the authors.
- Published
- 2018
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40. New Territory for an Old Disease: 5-Alpha-Reductase Type 2 Deficiency in Bulgaria.
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Andonova S, Robeva R, Vazharova R, Ledig S, Grozdanova L, Stefanova E, Bradinova I, Todorov T, Hadjidekov G, Sirakov M, Wieacker P, Kumanov P, and Savov A
- Subjects
- Bulgaria, Disorder of Sex Development, 46,XY genetics, Disorder of Sex Development, 46,XY metabolism, Disorders of Sex Development genetics, Humans, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase deficiency, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase genetics, Disorders of Sex Development metabolism, Membrane Proteins deficiency, Membrane Proteins genetics, Mutation genetics
- Abstract
Disorders/differences of sexual development (DSD) are a group of conditions, some of which can be clinically indistinguishable mainly due to their phenotypic variability. Defining the molecular basis of their wide spectrum is still in progress. The diagnosis of 5-alpha-reductase type 2 (5α-reductase-2) deficiency is difficult especially in newborns and pre-pubertal individuals, and as a result its frequency might be underestimated. In the present study, we describe the clinical characteristics and molecular defects in 3 nonrelated 5α-reductase-2 deficiency patients of Bulgarian descent. Sequencing analysis revealed the mutations p.Y188CfsX9 and p.G196S, and MLPA analysis showed a deletion of exon 1 in the SRD5A2 gene. The observed genetic substitutions were not detected in 76 additionally screened unrelated controls, but a heterozygous healthy carrier of the p.R171S mutation was found. This is the first study on the molecular basis of 5α-reductase-2 deficiency in Bulgaria. It suggests that the carrier frequency of mutations in the SRD5A2 gene might be noteworthy worldwide. There is no correlation between cultural aspects, location, and/or population size and the number of different mutations in SRD5A2 detected, and more efforts should be made to determine the prevalence of this condition in different geographic areas. Our study supports the importance of genetic testing in 46,XY DSD patients, especially in countries or regions where 5α-reductase-2 deficiency has not been reported so far., (© 2017 S. Karger AG, Basel.)
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- 2017
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41. Four Novel NR5A1 Mutations in 46,XY Gonadal Dysgenesis Patients Including Frameshift Mutations with Altered Subcellular SF-1 Localization.
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Rehkämper J, Tewes AC, Horvath J, Scherer G, Wieacker P, and Ledig S
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- Female, HEK293 Cells, Humans, Male, Mutation genetics, Retrospective Studies, Steroidogenic Factor 1 genetics, Frameshift Mutation genetics, Gonadal Dysgenesis, 46,XY genetics, Steroidogenic Factor 1 metabolism
- Abstract
46,XY gonadal dysgenesis (46,XY GD) is a disorder of sexual development caused by mutations in genes involved in early gonadal development (bipotential gonads) and testis differentiation. In 46,XY GD individuals, mutations of the SRY gene are detected most frequently, followed by mutations in the NR5A1 (SF-1) gene, but in a lot of cases, the underlying molecular mechanism remains elusive. In this study, we retrospectively performed sequence analyses of the NR5A1 (SF-1) gene in 84 patients with complete, partial, and syndromic forms of 46,XY GD. In total, 7 heterozygous mutations were found in 6 of 84 patients (7.1%). Among these, we identified 4 mutations that, to the best of our knowledge, have not been reported before (c.268G>T, c.369del, c.871-1G>C, and c.893T>C). Transfection of different mutations revealed altered subcellular localization of the mutant SF-1 protein in the case of the frameshift mutations, indicating an impaired protein function. In conclusion, we present 4 novel mutations of the NR5A1 gene associated with 46,XY GD together with in vitro data pointing towards a possible functional impairment of the mutant SF-1 proteins., (© 2017 S. Karger AG, Basel.)
- Published
- 2017
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42. Variations in RBM8A and TBX6 are associated with disorders of the müllerian ducts.
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Tewes AC, Rall KK, Römer T, Hucke J, Kapczuk K, Brucker S, Wieacker P, and Ledig S
- Subjects
- 46, XX Disorders of Sex Development diagnosis, Congenital Abnormalities diagnosis, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Heterozygote, Hospitals, University, Humans, Phenotype, Retrospective Studies, 46, XX Disorders of Sex Development genetics, Congenital Abnormalities genetics, Mullerian Ducts abnormalities, Mutation, RNA-Binding Proteins genetics, T-Box Domain Proteins genetics
- Abstract
Objective: To identify genetic causes of malformations of the müllerian ducts., Design: Retrospective laboratory study., Setting: University hospital., Patient(s): A total of 167 patients with disorders of the müllerian ducts: 116 patients with Mayer-Rokitansky-Küster-Hauser syndrome and 51 patients with fusion disorders of the müllerian ducts. The control group was composed of 94 fertile women with at least one child., Intervention(s): Sequential analysis of RBM8A and TBX6 in a group of 167 clinically well-defined patients with disorders of the müllerian ducts., Main Outcome Measure(s): Identification of rare variants in RBM8A and TBX6., Result(s): In total, we detected four RBM8A variants in 13 patients with disorders of the müllerian ducts and two heterozygous TBX6 variants in 5 of 167 patients., Conclusion(s): Mutations of RBM8A and TBX6 are associated with disorders of the müllerian ducts., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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43. A Novel SRY Gene Mutation p.F109L in a 46,XY Female with Complete Gonadal Dysgenesis.
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Andonova S, Robeva R, Sirakov M, Mainhard K, Tomova A, Ledig S, Kumanov P, and Savov A
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- Adolescent, Amino Acid Substitution, Base Sequence, DNA Mutational Analysis, Dysgerminoma genetics, Dysgerminoma pathology, Female, Gonadal Dysgenesis, 46,XY pathology, Gonadoblastoma genetics, Gonadoblastoma pathology, Humans, Mutation, Missense, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Sex-Determining Region Y Protein genetics, Genes, sry, Gonadal Dysgenesis, 46,XY genetics
- Abstract
46,XY complete gonadal dysgenesis (CGD) is a disorder of sexual development that can result from different mutations in genes associated with sex determination. Patients are phenotypically females, and the disease is often diagnosed in late adolescence because of delayed puberty. Here, we present the clinical and molecular data of a 46,XY female CGD patient with gonadoblastoma with dysgerminoma and incidentally found inherited thrombophilia. The clinical significance of the described de novo SRY gene mutation c.325T>C (p.F109L) is discussed. This case report supports the critical role of the HGM domain in the SRY gene and the need of a multidisciplinary approach for CGD patients., (© 2016 S. Karger AG, Basel.)
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- 2015
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44. Premature ovarian failure caused by a heterozygous missense mutation in POF1B and a reciprocal translocation 46,X,t(X;3)(q21.1;q21.3).
- Author
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Ledig S, Preisler-Adams S, Morlot S, Liehr T, and Wieacker P
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- Adult, Chromosome Banding, Female, Heterozygote, Humans, Microfilament Proteins, Polymerase Chain Reaction, X Chromosome Inactivation genetics, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, X genetics, Mutation, Missense genetics, Primary Ovarian Insufficiency genetics, Proteins genetics, Translocation, Genetic
- Abstract
In a patient affected by premature ovarian failure, a reciprocal translocation between chromosomes X and 3 and an additional heterozygous missense mutation in the X-linked gene POF1B were detected. Homozygosity for POF1B mutations is well-known to be associated with premature ovarian failure. In this case, the rare combination of skewed X inactivation due to the reciprocal translocation involving one X chromosome and heterozygosity for a known POF1B mutation explains the phenotype.
- Published
- 2015
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45. DMRT1 mutations are rarely associated with male infertility.
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Tewes AC, Ledig S, Tüttelmann F, Kliesch S, and Wieacker P
- Subjects
- Case-Control Studies, Gene Frequency, Humans, Male, Polymorphism, Single Nucleotide, Retrospective Studies, Sertoli Cell-Only Syndrome genetics, Azoospermia genetics, Oligospermia genetics, Point Mutation, Transcription Factors genetics
- Abstract
Objective: To study a potential association between male infertility and DMRT1 mutations., Design: Retrospective sequencing study., Setting: University hospital., Patient(s): 171 patients with cryptozoospermia (sperm concentration<0.1 million/mL, n=40) or nonobstructive azoospermia (n=131), and 215 normozoospermic controls., Intervention(s): Sequence analysis of DMRT1., Main Outcome Measure(s): Identification of rare variants in DMRT1 that are associated with male infertility., Result(s): In total, we detected four putative pathogenic mutations in six patients (3.5%) and less frequently in two controls (0.9%)., Conclusion(s): Point mutations of DMRT1 may be rarely associated with male infertility., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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46. Copy number variants in patients with severe oligozoospermia and Sertoli-cell-only syndrome.
- Author
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Tüttelmann F, Simoni M, Kliesch S, Ledig S, Dworniczak B, Wieacker P, and Röpke A
- Subjects
- Adult, Case-Control Studies, Chromosome Deletion, Chromosomes, Human, X genetics, Comparative Genomic Hybridization, Humans, Male, Middle Aged, Phenotype, Sequence Analysis, DNA, Spermatogenesis genetics, Azoospermia genetics, Gene Dosage, Infertility, Male genetics, Oligospermia genetics, Sertoli Cell-Only Syndrome genetics
- Abstract
A genetic origin is estimated in 30% of infertile men with the common phenotypes of oligo- or azoospermia, but the pathogenesis of spermatogenic failure remains frequently obscure. To determine the involvement of Copy Number Variants (CNVs) in the origin of male infertility, patients with idiopathic severe oligozoospermia (N = 89), Sertoli-cell-only syndrome (SCOS, N = 37)) and controls with normozoospermia (N = 100) were analysed by array-CGH using the 244A/400K array sets (Agilent Technologies). The mean number of CNVs and the amount of DNA gain/loss were comparable between all groups. Ten recurring CNVs were only found in patients with severe oligozoospermia, three only in SCOS and one CNV in both groups with spermatogenic failure but not in normozoospermic men. Sex-chromosomal, mostly private CNVs were significantly overrepresented in patients with SCOS. CNVs found several times in all groups were analysed in a case-control design and four additional candidate genes and two regions without known genes were associated with SCOS (P<1×10(-3)). In conclusion, by applying array-CGH to study male infertility for the first time, we provide a number of candidate genes possibly causing or being risk factors for the men's spermatogenic failure. The recurring, patient-specific and private, sex-chromosomal CNVs as well as those associated with SCOS are candidates for further, larger case-control and re-sequencing studies.
- Published
- 2011
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47. Recurrent aberrations identified by array-CGH in patients with Mayer-Rokitansky-Küster-Hauser syndrome.
- Author
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Ledig S, Schippert C, Strick R, Beckmann MW, Oppelt PG, and Wieacker P
- Subjects
- Case-Control Studies, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 22 genetics, Cohort Studies, Congenital Abnormalities, Female, Gene Frequency, Genetic Association Studies, Humans, Kidney abnormalities, Mullerian Ducts abnormalities, Somites abnormalities, Spine abnormalities, Uterus abnormalities, Vagina abnormalities, 46, XX Disorders of Sex Development genetics, Abnormalities, Multiple genetics, Chromosome Aberrations statistics & numerical data, Comparative Genomic Hybridization
- Abstract
Objective: To identify genetic causes of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome., Design: Prospective laboratory study., Setting: University hospital., Patient(s): Fifty-six patients with MRKH syndrome., Intervention(s): Identification of microdeletions and -duplications in a group of 48 MRKH patients by array-CGH. Results obtained by array-CGH were confirmed by RT-qPCR. Sequential analysis of two candidate genes LHX1 and HNF1B in a group of 56 MRKH patients., Main Outcome Measure(s): Identification of chromosomal regions and genes (recurrent and private) associated with MRKH syndrome., Result(s): We could delineate three definitively relevant regions (1q21.1, 17q12, and 22q11.21) and suggest that LHX1 und HNF1B are candidate genes for MRKH syndrome, because we identified recurrent deletions affecting these genes and a possible causative missense mutation in LHX1., Conclusion(s): Our findings suggest that different chromosomal regions are associated with MRKH syndrome., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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48. WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes.
- Author
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Bohring A, Stamm T, Spaich C, Haase C, Spree K, Hehr U, Hoffmann M, Ledig S, Sel S, Wieacker P, and Röpke A
- Subjects
- Ectodermal Dysplasia pathology, Ectodermal Dysplasia physiopathology, Female, Humans, Male, Pedigree, Sex Characteristics, Ectodermal Dysplasia genetics, Mutation, Wnt Proteins genetics
- Abstract
Odonto-onycho-dermal dysplasia (OODD), a rare autosomal-recessive inherited form of ectodermal dysplasia including severe oligodontia, nail dystrophy, palmoplantar hyperkeratosis, and hyperhidrosis, was recently shown to be caused by a homozygous nonsense WNT10A mutation in three consanguineous Lebanese families. Here, we report on 12 patients, from 11 unrelated families, with ectodermal dysplasia caused by five previously undescribed WNT10A mutations. In this study, we show that (1) WNT10A mutations cause not only OODD but also other forms of ectodermal dysplasia, reaching from apparently monosymptomatic severe oligodontia to Schöpf-Schulz-Passarge syndrome, which is so far considered a unique entity by the findings of numerous cysts along eyelid margins and the increased risk of benign and malignant skin tumors; (2) WNT10A mutations are a frequent cause of ectodermal dysplasia and were found in about 9% of an unselected patient cohort; (3) about half of the heterozygotes (53.8%) show a phenotype manifestation, including mainly tooth and nail anomalies, which was not reported before in OODD; and (4) heterozygotes show a sex-biased manifestation pattern, with a significantly higher proportion of tooth anomalies in males than in females, which may implicate gender-specific differences of WNT10A expression.
- Published
- 2009
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49. BMP15 mutations in XX gonadal dysgenesis and premature ovarian failure.
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Ledig S, Röpke A, Haeusler G, Hinney B, and Wieacker P
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- Adult, Base Sequence, Bone Morphogenetic Protein 15, Case-Control Studies, Female, Gene Expression Regulation, Developmental, Gonadal Dysgenesis, 46,XX diagnosis, Growth Differentiation Factor 9, Humans, Molecular Sequence Data, Polymerase Chain Reaction, Polymorphism, Genetic, Primary Ovarian Insufficiency diagnosis, Receptors, FSH genetics, Reference Values, Sensitivity and Specificity, Severity of Illness Index, Genetic Predisposition to Disease, Gonadal Dysgenesis, 46,XX genetics, Intercellular Signaling Peptides and Proteins genetics, Mutation, Primary Ovarian Insufficiency genetics
- Abstract
Objective: Premature ovarian failure (POF) is a heterogeneous group of diseases with amenorrhea before the age of 40 years and elevated gonadotropins. Recently, heterozygous mutations in the X-linked gene encoding bone morphogenetic protein-15 (BMP15) have been identified as a possible cause of ovarian failure., Study Design: Molecular analysis of BMP15, growth differentiation factor-9 (GDF9), and follicle-stimulating hormone receptor (FSHR) in patients with ovarian failure., Results: We can show that a BMP15 alteration, previously described as a mutation, is instead a polymorphism. A digenic inheritance of POF including BMP15 and FSHR is unlikely. Mutations in GDF9 could not be detected., Conclusion: Caution is recommended in the interpretation of BMP15 mutations in the context of POF.
- Published
- 2008
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50. Prenatal diagnosis of Roberts syndrome and detection of an ESCO2 frameshift mutation in a Pakistani family.
- Author
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Schulz S, Gerloff C, Ledig S, Langer D, Volleth M, Shirneshan K, and Wieacker P
- Subjects
- Amniocentesis, Craniofacial Abnormalities genetics, Cytogenetic Analysis, DNA analysis, Female, Growth Disorders genetics, Humans, Limb Deformities, Congenital genetics, Male, Pakistan, Pregnancy, Syndrome, Ultrasonography, Prenatal, Acetyltransferases genetics, Chromosomal Proteins, Non-Histone genetics, Frameshift Mutation genetics, Prenatal Diagnosis
- Abstract
Objectives: We report two siblings with Roberts syndrome (RBS), and an attempt to delineate the underlying molecular mechanism leading to familial recurrence., Methods: Cytogenetic studies and direct sequencing of the ESCO2 gene were carried out in the second affected fetus and the parents. Fetal DNA was obtained from amniocytes after amniocentesis. Parental DNA was obtained from peripheral blood samples., Results: Cytogenetic analysis of amniocytes revealed a normal male karyotype in 20 analyzed metaphases and chromosomal aneuploidies in 10 metaphases. All metaphases displayed premature separation of centromeres and puffing of heterochromatic regions near the centromere. A homozygous mutation leading to a frameshift in ESCO2 was identified in the fetal DNA sample. Both parents are heterozygous carriers of the same mutation., Conclusion: The present case demonstrates the prenatal diagnosis of RBS associated with a frameshift mutation in ESCO2.
- Published
- 2008
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