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1,103 results on '"Gailus-Durner, Valerie'

1. X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes

Author

Hasenbein, Tim P., Hoelzl, Sarah, Smith, Zachary D., Gerhardinger, Chiara, Gonner, Marion O. C., Aguilar-Pimentel, Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Dragano, Nathalia R. V., da Silva-Buttkus, Patricia, Garrett, Lillian, Hölter, Sabine M., Kraiger, Markus, Östereicher, Manuela A., Rathkolb, Birgit, Sanz-Moreno, Adrián, Spielmann, Nadine, Wurst, Wolfgang, Gailus-Durner, Valerie, Fuchs, Helmut, Hrabě de Angelis, Martin, Meissner, Alexander, Engelhardt, Stefan, Rinn, John L., and Andergassen, Daniel

Published
2024
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3. X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes

Author

Tim P. Hasenbein, Sarah Hoelzl, Zachary D. Smith, Chiara Gerhardinger, Marion O. C. Gonner, Antonio Aguilar-Pimentel, Oana V. Amarie, Lore Becker, Julia Calzada-Wack, Nathalia R. V. Dragano, Patricia da Silva-Buttkus, Lillian Garrett, Sabine M. Hölter, Markus Kraiger, Manuela A. Östereicher, Birgit Rathkolb, Adrián Sanz-Moreno, Nadine Spielmann, Wolfgang Wurst, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Alexander Meissner, Stefan Engelhardt, John L. Rinn, and Daniel Andergassen

Subjects
Science
Abstract

Abstract The lncRNA Crossfirre was identified as an imprinted X-linked gene, and is transcribed antisense to the trans-acting lncRNA Firre. The Firre locus forms an inactive-X-specific interaction with Dxz4, both loci providing the platform for the largest conserved chromatin structures. Here, we characterize the epigenetic profile of these loci, revealing them as the most female-specific accessible regions genome-wide. To address their in vivo role, we perform one of the largest X-linked knockout studies by deleting Crossfirre, Firre, and Dxz4 individually and in combination. Despite their distinct epigenetic features observed on the X chromosome, our allele-specific analysis uncovers these loci as dispensable for imprinted and random X chromosome inactivation. However, we provide evidence that Crossfirre affects autosomal gene regulation but only in combination with Firre. To shed light on the functional role of these sex-specific loci, we perform an extensive standardized phenotyping pipeline and uncover diverse knockout and sex-specific phenotypes. Collectively, our study provides the foundation for exploring the intricate interplay of conserved X-linked loci in vivo.

Published
2024
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4. Single-cell, whole-embryo phenotyping of mammalian developmental disorders

Author

Huang, Xingfan, Henck, Jana, Qiu, Chengxiang, Sreenivasan, Varun KA, Balachandran, Saranya, Amarie, Oana V, Hrabě de Angelis, Martin, Behncke, Rose Yinghan, Chan, Wing-Lee, Despang, Alexandra, Dickel, Diane E, Duran, Madeleine, Feuchtinger, Annette, Fuchs, Helmut, Gailus-Durner, Valerie, Haag, Natja, Hägerling, Rene, Hansmeier, Nils, Hennig, Friederike, Marshall, Cooper, Rajderkar, Sudha, Ringel, Alessa, Robson, Michael, Saunders, Lauren M, da Silva-Buttkus, Patricia, Spielmann, Nadine, Srivatsan, Sanjay R, Ulferts, Sascha, Wittler, Lars, Zhu, Yiwen, Kalscheuer, Vera M, Ibrahim, Daniel M, Kurth, Ingo, Kornak, Uwe, Visel, Axel, Pennacchio, Len A, Beier, David R, Trapnell, Cole, Cao, Junyue, Shendure, Jay, and Spielmann, Malte

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Human Genome, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Mice, Cell Nucleus, Developmental Disabilities, Embryo, Mammalian, Gain of Function Mutation, Genotype, Loss of Function Mutation, Models, Genetic, Mutation, Phenotype, Single-Cell Gene Expression Analysis, Disease Models, Animal, General Science & Technology
Abstract

Mouse models are a critical tool for studying human diseases, particularly developmental disorders1. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse2. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing3 to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions4,5. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.

Published
2023

5. TRPS1 maintains luminal progenitors in the mammary gland by repressing SRF/MRTF activity

Author

Marie Tollot-Wegner, Marco Jessen, KyungMok Kim, Adrián Sanz-Moreno, Nadine Spielmann, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, and Björn von Eyss

Subjects
TRPS1, YAP/TAZ, SRF, Mammary gland homeostasis, Luminal progenitor, Breast cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract The transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and is critical during puberty and pregnancy. Its function in the resting state remains however unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy adult mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. Using transcriptomic approaches, flow cytometry and functional assays, we show that TRPS1 activity is essential to maintain a functional luminal progenitor compartment. This requires the repression of both YAP/TAZ and SRF/MRTF activities. TRPS1 represses SRF/MRTF activity indirectly by modulating RhoA activity. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors intrinsically linked to mechanotransduction in the mammary gland. It may also provide new insights into the oncogenic functions of TRPS1 as luminal progenitors are likely the cells of origin of many breast cancers.

Published
2024
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6. Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT)

Author

Riedhammer, Korbinian M., Nguyen, Thanh-Minh T., Koşukcu, Can, Calzada-Wack, Julia, Li, Yong, Assia Batzir, Nurit, Saygılı, Seha, Wimmers, Vera, Kim, Gwang-Jin, Chrysanthou, Marialena, Bakey, Zeineb, Sofrin-Drucker, Efrat, Kraiger, Markus, Sanz-Moreno, Adrián, Amarie, Oana V., Rathkolb, Birgit, Klein-Rodewald, Tanja, Garrett, Lillian, Hölter, Sabine M., Seisenberger, Claudia, Haug, Stefan, Schlosser, Pascal, Marschall, Susan, Wurst, Wolfgang, Fuchs, Helmut, Gailus-Durner, Valerie, Wuttke, Matthias, Hrabe de Angelis, Martin, Ćomić, Jasmina, Akgün Doğan, Özlem, Özlük, Yasemin, Taşdemir, Mehmet, Ağbaş, Ayşe, Canpolat, Nur, Orenstein, Naama, Çalışkan, Salim, Weber, Ruthild G., Bergmann, Carsten, Jeanpierre, Cecile, Saunier, Sophie, Lim, Tze Y., Hildebrandt, Friedhelm, Alhaddad, Bader, Basel-Salmon, Lina, Borovitz, Yael, Wu, Kaman, Antony, Dinu, Matschkal, Julia, Schaaf, Christian W., Renders, Lutz, Schmaderer, Christoph, Rogg, Manuel, Schell, Christoph, Meitinger, Thomas, Heemann, Uwe, Köttgen, Anna, Arnold, Sebastian J., Ozaltin, Fatih, Schmidts, Miriam, and Hoefele, Julia

Published
2024
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8. Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice

Author

Oestereicher, Manuela A., Wotton, Janine M., Ayabe, Shinya, Bou About, Ghina, Cheng, Tsz Kwan, Choi, Jae-Hoon, Clary, Dave, Dew, Emily M., Elfertak, Lahcen, Guimond, Alain, Haseli Mashhadi, Hamed, Heaney, Jason D., Kelsey, Lois, Keskivali-Bond, Piia, Lopez Gomez, Federico, Marschall, Susan, McFarland, Michael, Meziane , Hamid, Munoz Fuentes, Violeta, Nam , Ki-Hoan, Nichtová, Zuzana, Pimm, Dale, Bower, Lynette, Prochazka, Jan, Rozman, Jan, Santos, Luis, Stewart, Michelle, Tanaka, Nobuhiko, Ward, Christopher S., Willett, Amelia M. E., Wilson, Robert, Braun, Robert E., Dickinson, Mary E., Flenniken, Ann M., Herault, Yann, Lloyd, K. C. Kent, Mallon, Ann-Marie, McKerlie, Colin, Murray, Stephen A., Nutter, Lauryl M. J., Sedlacek, Radislav, Seong, Je Kyung, Sorg, Tania, Tamura, Masaru, Wells, Sara, Schneltzer, Elida, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, White, Jacqueline K., and Spielmann, Nadine

Published
2023
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10. Knockout mouse models as a resource for the study of rare diseases

Author

da Silva-Buttkus, Patricia, Spielmann, Nadine, Klein-Rodewald, Tanja, Schütt, Christine, Aguilar-Pimentel, Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Garrett, Lillian, Gerlini, Raffaele, Kraiger, Markus, Leuchtenberger, Stefanie, Östereicher, Manuela A., Rathkolb, Birgit, Sanz-Moreno, Adrián, Stöger, Claudia, Hölter, Sabine M., Seisenberger, Claudia, Marschall, Susan, Fuchs, Helmut, Gailus-Durner, Valerie, and Hrabě de Angelis, Martin

Published
2023
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13. Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain

Author

Aguilar-Pimental, Juan A., Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Da Silva-Buttkus, Patricia, Dragano, Nathalia, Kraiger, Markus, Lengger, Christoph, Leuchtenberger, Stefanie, Marschall, Susan, Oestereicher, Manuela A., Rathkolb, Birgit, Sanz-Moreno, Adrián, Seisenberger, Claudia, Spielmann, Nadine, Stoeger, Claudia, Kumar, Vivek, Keskivali, Piia, King, Ruairidh, Haselimashhadi, Hamed, Bezginov, Alexandr, Norris, Clare, Taylor, Sarah, Pimm, Dale, Kelsey, Lois, Berberovic, Zorana, Qu, Dawei, D'Souza, Abigail, Bradaschia, Vivian, Eskandarian, Mohammed, Shang, Xueyuan, Duffin, Kyle, Roberton, Kyle, Xu, Catherine, Baguinat, Gloria, Laurin, Valerie, Lan, Qing, Sleep, Gillian, Lintott, Lauri, Gertsenstein, Marina, Tondat, Sandra, Cruz, Maribelle, Miller, David, Sorg, Tania, Riet, Fabrice, Tolentino, Heather, Tolentino, Todd, Schuchbauer, Mike, Hockenbury, Nichole, Beeman, Karrie, Pedroia, Sheryl, Salazar, Jason, Heffner, Mollie, Hsu, Joanne, Fletcher, Colin, Vanzanten, Maya, Golini, Elisabetta, Seavitt, John R., Lanza, Denise G., Lorenzo, Isabel, Gaspero, Angelina, Rios, Amanda, Garrett, Lillian, Trümbach, Dietrich, Lee, Donghyung, Mandillo, Silvia, Samaco, Rodney, Flenniken, Ann M., Stewart, Michelle, White, Jacqueline K., McKerlie, Colin, Nutter, Lauryl M.J., Vukobradovic, Igor, Veeraragavan, Surabi, Yuva, Lisa, Heaney, Jason D., Dickinson, Mary E., Meziane, Hamid, Hérault, Yann, Wells, Sara, Lloyd, K.C. Kent, Bower, Lynette, Lanoue, Louise, Clary, Dave, Zimprich, Annemarie, Gailus-Durner, Valerie, Fuchs, Helmut, Brown, Steve D.M., Chesler, Elissa J., Wurst, Wolfgang, Hrabě de Angelis, Martin, and Hölter, Sabine M.

Published
2024
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14. LncRNA U90926 is dispensable for the development of obesity‐associated phenotypes in vivo

Author

Bristy Sabikunnahar, Sydney Caldwell, Stella Varnum, Tyler Hogan, Karolyn G. Lahue, Birgit Rathkolb, Raffaele Gerlini, Nathalia R. V. Dragano, Antonio Aguilar‐Pimentel, Martin Irmler, Adrián Sanz‐Moreno, Patricia daSilva‐Buttkus, German Mouse Clinic Consortium, Johannes Beckers, Eckhard Wolf, Valerie Gailus‐Durner, Helmut Fuchs, Martin Hrabe de Angelis, Jennifer L. Ather, Matthew E. Poynter, and Dimitry N. Krementsov

Subjects
adipogenesis, LncRNA, obesity, U90926, Physiology, QP1-981
Abstract

Abstract Obesity is a global health problem characterized by excessive fat accumulation, driven by adipogenesis and lipid accumulation. Long non‐coding RNAs (lncRNAs) have recently been implicated in regulating adipogenesis and adipose tissue function. Mouse lncRNA U90926 was previously identified as a repressor of in vitro adipogenesis in 3T3‐L1 preadipocytes. Consequently, we hypothesized that, in vivo, U90926 may repress adipogenesis, and hence its deletion would increase weight gain and adiposity. We tested the hypothesis by applying U90926‐deficient (U9‐KO) mice to a high‐throughput phenotyping pipeline. Compared with WT, U9‐KO mice showed no major differences across a wide range of behavioral, neurological, and other physiological parameters. In mice fed a standard diet, we have found no differences in obesity‐related phenotypes, including weight gain, fat mass, and plasma concentrations of glucose, insulin, triglycerides, and free fatty acids, in U9‐KO mice compared to WT. U90926 deficiency lacked a major effect on white adipose tissue morphology and gene expression profile. Furthermore, in mice fed a high‐fat diet, we found increased expression of U90926 in adipose tissue stromal vascular cell fraction, yet observed no effect of U90926 deficiency on weight gain, fat mass, adipogenesis marker expression, and immune cell infiltration into the adipose tissue. These data suggest that the U90926 lacks an essential role in obesity‐related phenotypes and adipose tissue biology in vivo.

Published
2024
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15. AOX delays the onset of the lethal phenotype in a mouse model of Uqcrh (complex III) disease

Author

Jacobs, Howard T., Szibor, Marten, Rathkolb, Birgit, da Silva-Buttkus, Patricia, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Dragano, Nathalia, Garrett, Lillian, Gerlini, Raffaele, Hölter, Sabine M., Klein-Rodewald, Tanja, Kraiger, Markus, Leuchtenberger, Stefanie, Marschall, Susan, Östereicher, Manuela A., Pfannes, Kristina, Sanz-Moreno, Adrián, Seisenberger, Claudia, Spielmann, Nadine, Stoeger, Claudia, Wurst, Wolfgang, Fuchs, Helmut, Hrabě de Angelis, Martin, and Gailus-Durner, Valérie

Published
2023
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16. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease

Author

Calame, Daniel G., Guo, Tianyu, Wang, Chen, Garrett, Lillian, Jolly, Angad, Dawood, Moez, Kurolap, Alina, Henig, Noa Zunz, Fatih, Jawid M., Herman, Isabella, Du, Haowei, Mitani, Tadahiro, Becker, Lore, Rathkolb, Birgit, Gerlini, Raffaele, Seisenberger, Claudia, Marschall, Susan, Hunter, Jill V., Gerard, Amanda, Heidlebaugh, Alexis, Challman, Thomas, Spillmann, Rebecca C., Jhangiani, Shalini N., Coban-Akdemir, Zeynep, Lalani, Seema, Liu, Lingxiao, Revah-Politi, Anya, Iglesias, Alejandro, Guzman, Edwin, Baugh, Evan, Boddaert, Nathalie, Rondeau, Sophie, Ormieres, Clothide, Barcia, Giulia, Tan, Queenie K.G., Thiffault, Isabelle, Pastinen, Tomi, Sheikh, Kazim, Biliciler, Suur, Mei, Davide, Melani, Federico, Shashi, Vandana, Yaron, Yuval, Steele, Mary, Wakeling, Emma, Østergaard, Elsebet, Nazaryan-Petersen, Lusine, Millan, Francisca, Santiago-Sim, Teresa, Thevenon, Julien, Bruel, Ange-Line, Thauvin-Robinet, Christel, Popp, Denny, Platzer, Konrad, Gawlinski, Pawel, Wiszniewski, Wojciech, Marafi, Dana, Pehlivan, Davut, Posey, Jennifer E., Gibbs, Richard A., Gailus-Durner, Valerie, Guerrini, Renzo, Fuchs, Helmut, Hrabě de Angelis, Martin, Hölter, Sabine M., Cheung, Hoi-Hung, Gu, Shen, and Lupski, James R.

Published
2023
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17. Soft windowing application to improve analysis of high-throughput phenotyping data

Author

Haselimashhadi, Hamed, Mason, Jeremy C, Munoz-Fuentes, Violeta, López-Gómez, Federico, Babalola, Kolawole, Acar, Elif F, Kumar, Vivek, White, Jacqui, Flenniken, Ann M, King, Ruairidh, Straiton, Ewan, Seavitt, John Richard, Gaspero, Angelina, Garza, Arturo, Christianson, Audrey E, Hsu, Chih-Wei, Reynolds, Corey L, Lanza, Denise G, Lorenzo, Isabel, Green, Jennie R, Gallegos, Juan J, Bohat, Ritu, Samaco, Rodney C, Veeraragavan, Surabi, Kim, Jong Kyoung, Miller, Gregor, Fuchs, Helmult, Garrett, Lillian, Becker, Lore, Kang, Yeon Kyung, Clary, David, Cho, Soo Young, Tamura, Masaru, Tanaka, Nobuhiko, Soo, Kyung Dong, Bezginov, Alexandr, About, Ghina Bou, Champy, Marie-France, Vasseur, Laurent, Leblanc, Sophie, Meziane, Hamid, Selloum, Mohammed, Reilly, Patrick T, Spielmann, Nadine, Maier, Holger, Gailus-Durner, Valerie, Sorg, Tania, Hiroshi, Masuya, Yuichi, Obata, Heaney, Jason D, Dickinson, Mary E, Wolfgang, Wurst, Tocchini-Valentini, Glauco P, Lloyd, Kevin C Kent, McKerlie, Colin, Seong, Je Kyung, Yann, Herault, de Angelis, Martin Hrabé, Brown, Steve DM, Smedley, Damian, Flicek, Paul, Mallon, Ann-Marie, Parkinson, Helen, and Meehan, Terrence F

Subjects
Biological Sciences, Genetics, Animals, Genetic Association Studies, Humans, Mice, Phenotype, Population Health, Software, Mathematical Sciences, Information and Computing Sciences, Bioinformatics, Biological sciences, Information and computing sciences, Mathematical sciences
Abstract

MotivationHigh-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors.ResultsHere we introduce 'soft windowing', a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources.Availability and implementationThe method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin.Supplementary informationSupplementary data are available at Bioinformatics online.

Published
2020

18. Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice

Author

Kan Xie, Helmut Fuchs, Enzo Scifo, Dan Liu, Ahmad Aziz, Juan Antonio Aguilar-Pimentel, Oana Veronica Amarie, Lore Becker, Patricia da Silva-Buttkus, Julia Calzada-Wack, Yi-Li Cho, Yushuang Deng, A. Cole Edwards, Lillian Garrett, Christina Georgopoulou, Raffaele Gerlini, Sabine M. Hölter, Tanja Klein-Rodewald, Michael Kramer, Stefanie Leuchtenberger, Dimitra Lountzi, Phillip Mayer-Kuckuk, Lena L. Nover, Manuela A. Oestereicher, Clemens Overkott, Brandon L. Pearson, Birgit Rathkolb, Jan Rozman, Jenny Russ, Kristina Schaaf, Nadine Spielmann, Adrián Sanz-Moreno, Claudia Stoeger, Irina Treise, Daniele Bano, Dirk H. Busch, Jochen Graw, Martin Klingenspor, Thomas Klopstock, Beverly A. Mock, Paolo Salomoni, Carsten Schmidt-Weber, Marco Weiergräber, Eckhard Wolf, Wolfgang Wurst, Valérie Gailus-Durner, Monique M. B. Breteler, Martin Hrabě de Angelis, and Dan Ehninger

Subjects
Science
Abstract

Lifespan can be affected by both physiological ageing and specific sets of pathologies associated with old age. Here the authors report a resource of large-scale cross-sectional phenotyping of aging male mice at different time points to analyse a large set of phenotypes and molecular markers, including during genetic and diet interventions affecting lifespan.

Published
2022
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19. New C3H Kit N824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetrance

Author

Tanja Klein-Rodewald, Kateryna Micklich, Adrián Sanz-Moreno, Monica Tost, Julia Calzada-Wack, Thure Adler, Matthias Klaften, Sibylle Sabrautzki, Bernhard Aigner, Markus Kraiger, Valerie Gailus-Durner, Helmut Fuchs, German Mouse Clinic Consortium, Albert Gründer, Heike Pahl, Eckhard Wolf, Martin Hrabe de Angelis, and Birgit Rathkolb

Subjects
Medicine, Science
Abstract

Abstract Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H Kit N824K/WT mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous Kit-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression.

Published
2022
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20. GPR101 loss promotes insulin resistance and diet-induced obesity risk

Author

Garrett, Lillian, Irmler, Martin, Baljuls, Angela, Rathkolb, Birgit, Dragano, Nathalia, Gerlini, Raffaele, Sanz-Moreno, Adrián, Aguilar-Pimentel, Antonio, Becker, Lore, Kraiger, Markus, Reithmeir, Rosa, Beckers, Johannes, Calzada-Wack, Julia, Wurst, Wolfgang, Fuchs, Helmut, Gailus-Durner, Valerie, Zimmermann, Tina, Hölter, Sabine M., and de Angelis, Martin Hrabě

Published
2023
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21. Human and mouse essentiality screens as a resource for disease gene discovery

Author

Cacheiro, Pilar, Muñoz-Fuentes, Violeta, Murray, Stephen A, Dickinson, Mary E, Bucan, Maja, Nutter, Lauryl MJ, Peterson, Kevin A, Haselimashhadi, Hamed, Flenniken, Ann M, Morgan, Hugh, Westerberg, Henrik, Konopka, Tomasz, Hsu, Chih-Wei, Christiansen, Audrey, Lanza, Denise G, Beaudet, Arthur L, Heaney, Jason D, Fuchs, Helmut, Gailus-Durner, Valerie, Sorg, Tania, Prochazka, Jan, Novosadova, Vendula, Lelliott, Christopher J, Wardle-Jones, Hannah, Wells, Sara, Teboul, Lydia, Cater, Heather, Stewart, Michelle, Hough, Tertius, Wurst, Wolfgang, Sedlacek, Radislav, Adams, David J, Seavitt, John R, Tocchini-Valentini, Glauco, Mammano, Fabio, Braun, Robert E, McKerlie, Colin, Herault, Yann, de Angelis, Martin Hrabě, Mallon, Ann-Marie, Lloyd, KC Kent, Brown, Steve DM, Parkinson, Helen, Meehan, Terrence F, and Smedley, Damian

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Pediatric, Biotechnology, Human Genome, 2.1 Biological and endogenous factors, Generic health relevance, Good Health and Well Being, Animals, Disease, Genes, Essential, Genetic Association Studies, Genomics, Humans, Mice, Mice, Knockout, Genomics England Research Consortium, International Mouse Phenotyping Consortium
Abstract

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.

Published
2020

22. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Author

Swan, Anna L, Schütt, Christine, Rozman, Jan, del Mar Muñiz Moreno, Maria, Brandmaier, Stefan, Simon, Michelle, Leuchtenberger, Stefanie, Griffiths, Mark, Brommage, Robert, Keskivali-Bond, Piia, Grallert, Harald, Werner, Thomas, Teperino, Raffaele, Becker, Lore, Miller, Gregor, Moshiri, Ala, Seavitt, John R, Cissell, Derek D, Meehan, Terrence F, Acar, Elif F, Lelliott, Christopher J, Flenniken, Ann M, Champy, Marie-France, Sorg, Tania, Ayadi, Abdel, Braun, Robert E, Cater, Heather, Dickinson, Mary E, Flicek, Paul, Gallegos, Juan, Ghirardello, Elena J, Heaney, Jason D, Jacquot, Sylvie, Lally, Connor, Logan, John G, Teboul, Lydia, Mason, Jeremy, Spielmann, Nadine, McKerlie, Colin, Murray, Stephen A, Nutter, Lauryl MJ, Odfalk, Kristian F, Parkinson, Helen, Prochazka, Jan, Reynolds, Corey L, Selloum, Mohammed, Spoutil, Frantisek, Svenson, Karen L, Vales, Taylor S, Wells, Sara E, White, Jacqueline K, Sedlacek, Radislav, Wurst, Wolfgang, Lloyd, KC Kent, Croucher, Peter I, Fuchs, Helmut, Williams, Graham R, Bassett, JH Duncan, Gailus-Durner, Valerie, Herault, Yann, Mallon, Ann-Marie, Brown, Steve DM, Mayer-Kuckuk, Philipp, and Hrabe de Angelis, Martin

Subjects
Biological Sciences, Genetics, Aging, Osteoporosis, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Musculoskeletal, Animals, Bone Density, Female, Gene Expression Regulation, Gene Ontology, Genetic Pleiotropy, Genome-Wide Association Study, Genotype, Male, Mice, Mice, Transgenic, Mutation, Osteoblasts, Osteoclasts, Phenotype, Promoter Regions, Genetic, Protein Interaction Maps, Sex Characteristics, Transcriptome, IMPC Consortium, Developmental Biology
Abstract

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

Published
2020

23. Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model

Author

Surabhi Kandaswamy, Lena Zobel, Bina John, Sathiyavedu Thyagarajan Santhiya, Jacqueline Bogedein, Gerhard K. H. Przemeck, Valérie Gailus-Durner, Helmut Fuchs, Martin Biel, Martin Hrabĕ de Angelis, Jochen Graw, Stylianos Michalakis, and Oana Veronica Amarie

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract

Abstract Retinitis pigmentosa is a group of progressive inherited retinal dystrophies that may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. In an Indian family suffering from retinitis pigmentosa, we identified a missense variation in CNGA1 affecting the cyclic nucleotide binding domain (CNBD) and characterized a mouse model developed with mutated CNBD. A gene panel analysis comprising 105 known RP genes was used to analyze a family with autosomal-recessive retinitis pigmentosa (arRP) and revealed that CNGA1 was affected. From sperm samples of ENU mutagenesis derived F1 mice, we re-derived a mutant with a Cnga1 mutation. Homozygous mutant mice, developing retinal degeneration, were examined for morphological and functional consequences of the mutation. In the family, we identified a rare CNGA1 variant (NM_001379270.1) c.1525 G > A; (p.Gly509Arg), which co-segregated among the affected family members. Homozygous Cnga1 mice harboring a (ENSMUST00000087213.12) c.1526 A > G (p.Tyr509Cys) mutation showed progressive degeneration in the retinal photoreceptors from 8 weeks on. This study supports a role for CNGA1 as a disease gene for arRP and provides new insights on the pathobiology of cGMP-binding domain mutations in CNGA1-RP.

Published
2022
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24. Monitoring longitudinal disease progression in a novel murine Kit tumor model using high-field MRI

Author

Markus Kraiger, Tanja Klein-Rodewald, Birgit Rathkolb, Julia Calzada-Wack, Adrián Sanz-Moreno, Helmut Fuchs, Eckhard Wolf, Valérie Gailus-Durner, and Martin Hrabě de Angelis

Subjects
Medicine, Science
Abstract

Abstract Animal models are an indispensable platform used in various research disciplines, enabling, for example, studies of basic biological mechanisms, pathological processes and new therapeutic interventions. In this study, we applied magnetic resonance imaging (MRI) to characterize the clinical picture of a novel N-ethyl-N-nitrosourea-induced Kit-mutant mouse in vivo. Seven C3H Kit N824K/WT mutant animals each of both sexes and their littermates were monitored every other month for a period of twelve months. MRI relaxometry data of hematopoietic bone marrow and splenic tissue as well as high-resolution images of the gastrointestinal organs were acquired. Compared with controls, the mutants showed a dynamic change in the shape and volume of the cecum and enlarged Peyer´s patches were identified throughout the entire study. Mammary tumors were observed in the majority of mutant females and were first detected at eight months of age. Using relaxation measurements, a substantial decrease in longitudinal relaxation times in hematopoietic tissue was detected in mutants at one year of age. In contrast, transverse relaxation time of splenic tissue showed no differences between genotypes, except in two mutant mice, one of which had leukemia and the other hemangioma. In this study, in vivo MRI was used for the first time to thoroughly characterize the evolution of systemic manifestations of a novel Kit-induced tumor model and to document the observable organ-specific disease cascade.

Published
2022
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25. Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome

Author

Maity-Kumar, Gandhari, Ständer, Lisa, DeAngelis, Meri, Lee, Sooyeon, Molenaar, Anna, Becker, Lore, Garrett, Lillian, Amerie, Oana V., Hoelter, Sabine M., Wurst, Wolfgang, Fuchs, Helmut, Feuchtinger, Annette, Gailus-Durner, Valerie, Garcia-Caceres, Cristina, Othman, Ahmed E., Brockmann, Caroline, Schöffling, Vanessa I., Beiser, Katja, Krude, Heiko, Mroz, Piotr A., Hofmann, Susanna, Tuckermann, Jan, DiMarchi, Richard D., Hrabe de Angelis, Martin, Tschöp, Matthias H., Pfluger, Paul T., and Müller, Timo D.

Published
2022
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28. Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse

Author

Annika Müller-Eigner, Adrián Sanz-Moreno, Irene de-Diego, Anuroop Venkateswaran Venkatasubramani, Martina Langhammer, Raffaele Gerlini, Birgit Rathkolb, Antonio Aguilar-Pimentel, Tanja Klein-Rodewald, Julia Calzada-Wack, Lore Becker, Sergio Palma-Vera, Benedikt Gille, Ignasi Forne, Axel Imhof, Chen Meng, Christina Ludwig, Franziska Koch, John T. Heiker, Angela Kuhla, Vanessa Caton, Julia Brenmoehl, Henry Reyer, Jennifer Schoen, Helmut Fuchs, Valerie Gailus-Durner, Andreas Hoeflich, Martin Hrabe de Angelis, and Shahaf Peleg

Subjects
Biology (General), QH301-705.5
Abstract

This study further characterizes the non-inbred Titan (also known as DU6) mouse line, which could be a useful model for obesity research.

Published
2022
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30. Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author

Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin

Published
2022
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33. Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse

Author

Müller-Eigner, Annika, Sanz-Moreno, Adrián, de-Diego, Irene, Venkatasubramani, Anuroop Venkateswaran, Langhammer, Martina, Gerlini, Raffaele, Rathkolb, Birgit, Aguilar-Pimentel, Antonio, Klein-Rodewald, Tanja, Calzada-Wack, Julia, Becker, Lore, Palma-Vera, Sergio, Gille, Benedikt, Forne, Ignasi, Imhof, Axel, Meng, Chen, Ludwig, Christina, Koch, Franziska, Heiker, John T., Kuhla, Angela, Caton, Vanessa, Brenmoehl, Julia, Reyer, Henry, Schoen, Jennifer, Fuchs, Helmut, Gailus-Durner, Valerie, Hoeflich, Andreas, de Angelis, Martin Hrabe, and Peleg, Shahaf

Published
2022
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35. Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice

Author

Xie, Kan, Fuchs, Helmut, Scifo, Enzo, Liu, Dan, Aziz, Ahmad, Aguilar-Pimentel, Juan Antonio, Amarie, Oana Veronica, Becker, Lore, da Silva-Buttkus, Patricia, Calzada-Wack, Julia, Cho, Yi-Li, Deng, Yushuang, Edwards, A. Cole, Garrett, Lillian, Georgopoulou, Christina, Gerlini, Raffaele, Hölter, Sabine M., Klein-Rodewald, Tanja, Kramer, Michael, Leuchtenberger, Stefanie, Lountzi, Dimitra, Mayer-Kuckuk, Phillip, Nover, Lena L., Oestereicher, Manuela A., Overkott, Clemens, Pearson, Brandon L., Rathkolb, Birgit, Rozman, Jan, Russ, Jenny, Schaaf, Kristina, Spielmann, Nadine, Sanz-Moreno, Adrián, Stoeger, Claudia, Treise, Irina, Bano, Daniele, Busch, Dirk H., Graw, Jochen, Klingenspor, Martin, Klopstock, Thomas, Mock, Beverly A., Salomoni, Paolo, Schmidt-Weber, Carsten, Weiergräber, Marco, Wolf, Eckhard, Wurst, Wolfgang, Gailus-Durner, Valérie, Breteler, Monique M. B., Hrabě de Angelis, Martin, and Ehninger, Dan

Published
2022
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36. Co-expression of prepulse inhibition and schizophrenia genes in the mouse and human brain

Author

Garrett, Lillian, primary, Trümbach, Dietrich, additional, Lee, Dongyhung, additional, Mandillo, Silvia, additional, Samaco, Rodney, additional, Flenniken, Ann M., additional, Stewart, Michelle, additional, Aguilar-Pimental, Juan A., additional, Amarie, Oana V., additional, Becker, Lore, additional, Calzada-Wack, Julia, additional, Da Silva-Buttkus, Patricia, additional, Dragano, Nathalia, additional, Kraiger, Markus, additional, Lengger, Christoph, additional, Leuchtenberger, Stefanie, additional, Marschall, Susan, additional, Oestereicher, Manuela A., additional, Rathkolb, Birgit, additional, Sanz-Moreno, Adrián, additional, Seisenberger, Claudia, additional, Spielmann, Nadine, additional, Stoeger, Claudia, additional, Kumar, Vivek, additional, Keskivali, Piia, additional, King, Ruairidh, additional, Haselimashhadi, Hamed, additional, Bezginov, Alexandr, additional, Norris, Clare, additional, Taylor, Sarah, additional, Pimm, Dale, additional, Kelsey, Lois, additional, Berberovic, Zorana, additional, Qu, Dawei, additional, D'Souza, Abigail, additional, Bradaschia, Vivian, additional, Eskandarian, Mohammed, additional, Shang, Xueyuan, additional, Duffin, Kyle, additional, Roberton, Kyle, additional, Xu, Catherine, additional, Baguinat, Gloria, additional, Laurin, Valerie, additional, Lan, Qing, additional, Sleep, Gillian, additional, Lintott, Lauri, additional, Gertsenstein, Marina, additional, Tondat, Sandra, additional, Cruz, Maribelle, additional, Miller, David, additional, Sorg, Tania, additional, Riet, Fabrice, additional, Tolentino, Heather, additional, Tolentino, Todd, additional, Schuchbauer, Mike, additional, Hockenbury, Nichole, additional, Beeman, Karrie, additional, Pedroia, Sheryl, additional, Salazar, Jason, additional, Heffner, Mollie, additional, Hsu, Joanne, additional, Fletcher, Colin, additional, Vanzanten, Maya, additional, Golini, Elisabetta, additional, Seavitt, John R., additional, Lanza, Denise G., additional, Lorenzo, Isabel, additional, Gaspero, Angelina, additional, Rios, Amanda, additional, White, Jacqueline K., additional, McKerlie, Colin, additional, Nutter, Lauryl M.J., additional, Vukobradovic, Igor, additional, Veeraragavan, Surabi, additional, Yuva, Lisa, additional, Heaney, Jason D., additional, Dickinson, Mary E., additional, Meziane, Hamid, additional, Hérault, Yann, additional, Wells, Sara, additional, Lloyd, K.C.Kent, additional, Bower, Lynette, additional, Lanoue, Louise, additional, Clary, Dave, additional, Zimprich, Annemarie, additional, Gailus-Durner, Valerie, additional, Fuchs, Helmut, additional, Brown, Steve D.M., additional, Chesler, Elissa J., additional, Wurst, Wolfgang, additional, Hrabě de Angelis, Martin, additional, and Hölter, Sabine M., additional

Published
2024
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37. Characterising a homozygous two‐exon deletion in UQCRH: comparing human and mouse phenotypes

Author

Silvia Vidali, Raffaele Gerlini, Kyle Thompson, Jill E Urquhart, Jana Meisterknecht, Juan Antonio Aguilar‐Pimentel, Oana V Amarie, Lore Becker, Catherine Breen, Julia Calzada‐Wack, Nirav F Chhabra, Yi‐Li Cho, Patricia da Silva‐Buttkus, René G Feichtinger, Kristine Gampe, Lillian Garrett, Kai P Hoefig, Sabine M Hölter, Elisabeth Jameson, Tanja Klein‐Rodewald, Stefanie Leuchtenberger, Susan Marschall, Philipp Mayer‐Kuckuk, Gregor Miller, Manuela A Oestereicher, Kristina Pfannes, Birgit Rathkolb, Jan Rozman, Charlotte Sanders, Nadine Spielmann, Claudia Stoeger, Marten Szibor, Irina Treise, John H Walter, Wolfgang Wurst, Johannes A Mayr, Helmut Fuchs, Ulrich Gärtner, Ilka Wittig, Robert W Taylor, William G Newman, Holger Prokisch, Valerie Gailus‐Durner, and Martin Hrabě de Angelis

Subjects
complex III, mitochondrial disease, mouse model, OXPHOS, UQCRH, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh−/−), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non‐episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh−/− mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (SXL), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh−/− mouse is a valuable model for future studies of human CIII deficiency.

Published
2021
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38. Publisher Correction: Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author

Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin

Published
2022
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39. Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome

Author

Gandhari Maity-Kumar, Lisa Ständer, Meri DeAngelis, Sooyeon Lee, Anna Molenaar, Lore Becker, Lillian Garrett, Oana V. Amerie, Sabine M. Hoelter, Wolfgang Wurst, Helmut Fuchs, Annette Feuchtinger, Valerie Gailus-Durner, Cristina Garcia-Caceres, Ahmed E. Othman, Caroline Brockmann, Vanessa I. Schöffling, Katja Beiser, Heiko Krude, Piotr A. Mroz, Susanna Hofmann, Jan Tuckermann, Richard D. DiMarchi, Martin Hrabe de Angelis, Matthias H. Tschöp, Paul T. Pfluger, and Timo D. Müller

Subjects
Allan-Herndon Dudley Syndrome, Thyroid hormone, Mct8, Oatp1c1, Energy metabolism, Myelination, Internal medicine, RC31-1245
Abstract

Objective: The Allan-Herndon-Dudley syndrome (AHDS) is a severe disease caused by dysfunctional central thyroid hormone transport due to functional loss of the monocarboxylate transporter 8 (MCT8). In this study, we assessed whether mice with concomitant deletion of the thyroid hormone transporters Mct8 and the organic anion transporting polypeptide (Oatp1c1) represent a valid preclinical model organism for the AHDS. Methods: We generated and metabolically characterized a new CRISPR/Cas9 generated Mct8/Oatp1c1 double-knockout (dKO) mouse line for the clinical features observed in patients with AHDS. Results: We show that Mct8/Oatp1c1 dKO mice mimic key hallmarks of the AHDS, including decreased life expectancy, central hypothyroidism, peripheral hyperthyroidism, impaired neuronal myelination, impaired motor abilities and enhanced peripheral thyroid hormone action in the liver, adipose tissue, skeletal muscle and bone. Conclusions: We conclude that Mct8/Oatp1c1 dKO mice are a valuable model organism for the preclinical evaluation of drugs designed to treat the AHDS.

Published
2022
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40. Seizures, ataxia and parvalbumin-expressing interneurons respond to selenium supply in Selenop-deficient mice

Author

Ulrich Schweizer, Eva K. Wirth, Thomas Klopstock, Sabine M. Hölter, Lore Becker, Jackob Moskovitz, Tilman Grune, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Josef Köhrle, and Lutz Schomburg

Subjects
Epilepsy, PVALB, Selenoprotein, Brain, Dystonia, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Mice with constitutive disruption of the Selenop gene have been key to delineate the importance of selenoproteins in neurobiology. However, the phenotype of this mouse model is exquisitely dependent on selenium supply and timing of selenium supplementation. Combining biochemical, histological, and behavioral methods, we tested the hypothesis that parvalbumin-expressing interneurons in the primary somatosensory cortex and hippocampus depend on dietary selenium availability in Selenop−/− mice. Selenop-deficient mice kept on adequate selenium diet (0.15 mg/kg, i.e. the recommended dietary allowance, RDA) developed ataxia, tremor, and hyperexcitability between the age of 4–5 weeks. Video-electroencephalography demonstrated epileptic seizures in Selenop−/− mice fed the RDA diet, while Selenop ± heterozygous mice behaved normally. Both neurological phenotypes, hyperexcitability/seizures and ataxia/dystonia were successfully prevented by selenium supplementation from birth or transgenic expression of human SELENOP under a hepatocyte-specific promoter. Selenium supplementation with 10 μM selenite in the drinking water on top of the RDA diet increased the activity of glutathione peroxidase in the brains of Selenop−/− mice to control levels. The effects of selenium supplementation on the neurological phenotypes were dose- and time-dependent. Selenium supplementation after weaning was apparently too late to prevent ataxia/dystonia, while selenium withdrawal from rescued Selenop−/− mice eventually resulted in ataxia. We conclude that SELENOP expression is essential for preserving interneuron survival under limiting Se supply, while SELENOP appears dispensable under sufficiently high Se status.

Published
2022
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41. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author

Rozman, Jan, Rathkolb, Birgit, Oestereicher, Manuela A, Schütt, Christine, Ravindranath, Aakash Chavan, Leuchtenberger, Stefanie, Sharma, Sapna, Kistler, Martin, Willershäuser, Monja, Brommage, Robert, Meehan, Terrence F, Mason, Jeremy, Haselimashhadi, Hamed, IMPC Consortium, Hough, Tertius, Mallon, Ann-Marie, Wells, Sara, Santos, Luis, Lelliott, Christopher J, White, Jacqueline K, Sorg, Tania, Champy, Marie-France, Bower, Lynette R, Reynolds, Corey L, Flenniken, Ann M, Murray, Stephen A, Nutter, Lauryl MJ, Svenson, Karen L, West, David, Tocchini-Valentini, Glauco P, Beaudet, Arthur L, Bosch, Fatima, Braun, Robert B, Dobbie, Michael S, Gao, Xiang, Herault, Yann, Moshiri, Ala, Moore, Bret A, Kent Lloyd, KC, McKerlie, Colin, Masuya, Hiroshi, Tanaka, Nobuhiko, Flicek, Paul, Parkinson, Helen E, Sedlacek, Radislav, Seong, Je Kyung, Wang, Chi-Kuang Leo, Moore, Mark, Brown, Steve D, Tschöp, Matthias H, Wurst, Wolfgang, Klingenspor, Martin, Wolf, Eckhard, Beckers, Johannes, Machicao, Fausto, Peter, Andreas, Staiger, Harald, Häring, Hans-Ulrich, Grallert, Harald, Campillos, Monica, Maier, Holger, Fuchs, Helmut, Gailus-Durner, Valerie, Werner, Thomas, and Hrabe de Angelis, Martin

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Nutrition, Human Genome, 2.1 Biological and endogenous factors, Generic health relevance, Animals, Area Under Curve, Basal Metabolism, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Gene Regulatory Networks, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Metabolic Diseases, Mice, Mice, Knockout, Obesity, Oxygen Consumption, Phenotype, Triglycerides, IMPC Consortium
Abstract

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.

Published
2018

42. Offspring born to influenza A virus infected pregnant mice have increased susceptibility to viral and bacterial infections in early life

Author

Henning Jacobsen, Kerstin Walendy-Gnirß, Nilgün Tekin-Bubenheim, Nancy Mounogou Kouassi, Isabel Ben-Batalla, Nikolaus Berenbrok, Martin Wolff, Vinicius Pinho dos Reis, Martin Zickler, Lucas Scholl, Annette Gries, Hanna Jania, Andreas Kloetgen, Arne Düsedau, Gundula Pilnitz-Stolze, Aicha Jeridi, Ali Önder Yildirim, Helmut Fuchs, Valerie Gailus-Durner, Claudia Stoeger, Martin Hrabe de Angelis, Tatjana Manuylova, Karin Klingel, Fiona J. Culley, Jochen Behrends, Sonja Loges, Bianca Schneider, Susanne Krauss-Etschmann, Peter Openshaw, and Gülsah Gabriel

Subjects
Science
Abstract

Influenza infection during pregnancy can affect health of offspring but it is not clear how this affects immune responses. Here the authors use a mouse model to show that influenza infection during pregnancy can increase susceptibility to secondary infection and alter immune cell function in offspring.

Published
2021
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43. Creld1 regulates myocardial development and function

Author

Beckert, Vera, Rassmann, Sebastian, Kayvanjoo, Amir Hossein, Klausen, Christina, Bonaguro, Lorenzo, Botermann, Dominik Simon, Krause, Melanie, Moreth, Kristin, Spielmann, Nadine, da Silva-Buttkus, Patricia, Fuchs, Helmut, Gailus-Durner, Valerie, de Angelis, Martin Hrabě, Händler, Kristian, Ulas, Thomas, Aschenbrenner, Anna C., Mass, Elvira, and Wachten, Dagmar

Published
2021
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44. Correction: Corrigendum: High-throughput discovery of novel developmental phenotypes

Author

Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie Helmut Fuchs, Sarah M, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Nutter, Susan Newbigging Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, Wurst, Wolfgang, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, and Murray, Maja Bućan Stephen A

Subjects
International Mouse Phenotyping Consortium, General Science & Technology
Abstract

This corrects the article DOI: 10.1038/nature19356.

Published
2017

45. Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium.

Author

Meehan, Terrence F, Conte, Nathalie, West, David B, Jacobsen, Julius O, Mason, Jeremy, Warren, Jonathan, Chen, Chao-Kung, Tudose, Ilinca, Relac, Mike, Matthews, Peter, Karp, Natasha, Santos, Luis, Fiegel, Tanja, Ring, Natalie, Westerberg, Henrik, Greenaway, Simon, Sneddon, Duncan, Morgan, Hugh, Codner, Gemma F, Stewart, Michelle E, Brown, James, Horner, Neil, International Mouse Phenotyping Consortium, Haendel, Melissa, Washington, Nicole, Mungall, Christopher J, Reynolds, Corey L, Gallegos, Juan, Gailus-Durner, Valerie, Sorg, Tania, Pavlovic, Guillaume, Bower, Lynette R, Moore, Mark, Morse, Iva, Gao, Xiang, Tocchini-Valentini, Glauco P, Obata, Yuichi, Cho, Soo Young, Seong, Je Kyung, Seavitt, John, Beaudet, Arthur L, Dickinson, Mary E, Herault, Yann, Wurst, Wolfgang, de Angelis, Martin Hrabe, Lloyd, KC Kent, Flenniken, Ann M, Nutter, Lauryl MJ, Newbigging, Susan, McKerlie, Colin, Justice, Monica J, Murray, Stephen A, Svenson, Karen L, Braun, Robert E, White, Jacqueline K, Bradley, Allan, Flicek, Paul, Wells, Sara, Skarnes, William C, Adams, David J, Parkinson, Helen, Mallon, Ann-Marie, Brown, Steve DM, and Smedley, Damian

Subjects
International Mouse Phenotyping Consortium, Animals, Mice, Knockout, Humans, Mice, Genetic Diseases, Inborn, Disease Models, Animal, Genetic Predisposition to Disease, Phenotype, Female, Male, Gene Knockout Techniques, Knockout, Genetic Diseases, Inborn, Disease Models, Animal, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.

Published
2017

46. A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse

Author

Biagosch, Caroline A., Vidali, Silvia, Faerberboeck, Michael, Hensler, Svenja-Viola, Becker, Lore, Amarie, Oana V., Aguilar-Pimentel, Antonio, Garrett, Lillian, Klein-Rodewald, Tanja, Rathkolb, Birgit, Zanuttigh, Enrica, Calzada-Wack, Julia, da Silva-Buttkus, Patricia, Rozman, Jan, Treise, Irina, Fuchs, Helmut, Gailus-Durner, Valerie, de Angelis, Martin Hrabě, Janik, Dirk, Wurst, Wolfgang, Mayr, Johannes A., Klopstock, Thomas, Meitinger, Thomas, Prokisch, Holger, and Iuso, Arcangela

Published
2021
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48. Costs of Implementing Quality in Research Practice

Author

Meagan Littrell, O., Stoeger, Claudia, Maier, Holger, Fuchs, Helmut, Hrabě de Angelis, Martin, Cassis, Lisa A., Gerhardt, Greg A., Grondin, Richard, Gailus-Durner, Valérie, Barrett, James E., Editor-in-Chief, Flockerzi, Veit, Editorial Board Member, Frohman, Michael A., Editorial Board Member, Geppetti, Pierangelo, Editorial Board Member, Hofmann, Franz B., Editorial Board Member, Michel, Martin C., Editorial Board Member, Page, Clive P., Editorial Board Member, Rosenthal, Walter, Editorial Board Member, Wang, KeWei, Editorial Board Member, Bespalov, Anton, editor, and Steckler, Thomas, editor

Published
2020
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49. Comparative Phenotyping of Mice Reveals Canonical and Noncanonical Physiological Functions of TRα and TRβ.

Author

Hönes, Georg Sebastian, Geist, Daniela, Wenzek, Christina, Pfluger, Paul Thomas, Müller, Timo Dirk, Aguilar-Pimentel, Juan Antonio, Amarie, Oana Veronica, Becker, Lore, Dragano, Natalia, Garrett, Lillian, Hölter, Sabine Maria, Rathkolb, Birgit, Rozman, Jan, Spielmann, Nadine, Treise, Irina, Wolf, Eckhard, Wurst, Wolfgang, Fuchs, Helmut, Gailus-Durner, Valerie, and Angelis, Martin Hrabe de

Subjects
ACTION spectrum, THYROID hormone receptors, MICE, MUSCLE metabolism, KNOCKOUT mice
Abstract

Thyroid hormone (TH) effects are mediated through TH receptors (TRs), TRα1, TRβ1, and TRβ2. The TRs bind to the DNA and regulate expression of TH target genes (canonical signaling). In addition, they mediate activation of signaling pathways (noncanonical signaling). Whether noncanonical TR action contributes to the spectrum of TH effects is largely unknown. The aim of this study was to attribute physiological effects to the TR isoforms and their canonical and noncanonical signaling. We conducted multiparameter phenotyping in male and female TR knockout mice (TRαKO, TRβKO), mice with disrupted canonical signaling due to mutations in the TR DNA binding domain (TRαGS, TRβGS), and their wild-type littermates. Perturbations in senses, especially hearing (mainly TRβ with a lesser impact of TRα), visual acuity, retinal thickness (TRα and TRβ), and in muscle metabolism (TRα) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little phenotypic consequence, suggesting that noncanonical TR action sufficed to maintain the wild-type phenotype for specific effects. For instance, macrocytic anemia, reduced retinal vascularization, or increased anxiety-related behavior were only observed in TRαKO but not TRαGS mice. Noncanonical TRα action improved energy utilization and prevented hyperphagia observed in female TRαKO mice. In summary, by examining the phenotypes of TRα and TRβ knockout models alongside their DNA binding–deficient mutants and wild-type counterparts, we could establish that the noncanonical actions of TRα and TRβ play a crucial role in modulating sensory, behavioral, and metabolic functions and, thus, contribute to the spectrum of physiological TH effects. [ABSTRACT FROM AUTHOR]

Published
2024
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50. Mice lacking the mitochondrial exonuclease MGME1 develop inflammatory kidney disease with glomerular dysfunction.

Author

Dusanka Milenkovic, Adrián Sanz-Moreno, Julia Calzada-Wack, Birgit Rathkolb, Oana Veronica Amarie, Raffaele Gerlini, Antonio Aguilar-Pimentel, Jelena Misic, Marie-Lune Simard, Eckhard Wolf, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě de Angelis, and Nils-Göran Larsson

Subjects
Genetics, QH426-470
Abstract

Mitochondrial DNA (mtDNA) maintenance disorders are caused by mutations in ubiquitously expressed nuclear genes and lead to syndromes with variable disease severity and tissue-specific phenotypes. Loss of function mutations in the gene encoding the mitochondrial genome and maintenance exonuclease 1 (MGME1) result in deletions and depletion of mtDNA leading to adult-onset multisystem mitochondrial disease in humans. To better understand the in vivo function of MGME1 and the associated disease pathophysiology, we characterized a Mgme1 mouse knockout model by extensive phenotyping of ageing knockout animals. We show that loss of MGME1 leads to de novo formation of linear deleted mtDNA fragments that are constantly made and degraded. These findings contradict previous proposal that MGME1 is essential for degradation of linear mtDNA fragments and instead support a model where MGME1 has a critical role in completion of mtDNA replication. We report that Mgme1 knockout mice develop a dramatic phenotype as they age and display progressive weight loss, cataract and retinopathy. Surprisingly, aged animals also develop kidney inflammation, glomerular changes and severe chronic progressive nephropathy, consistent with nephrotic syndrome. These findings link the faulty mtDNA synthesis to severe inflammatory disease and thus show that defective mtDNA replication can trigger an immune response that causes age-associated progressive pathology in the kidney.

Published
2022
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