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8 results on '"Leuchtenberger, Stefanie"'

1. Understanding gene functions and disease mechanisms: Phenotyping pipelines in the German Mouse Clinic.

Author

Fuchs H, Aguilar-Pimentel JA, Amarie OV, Becker L, Calzada-Wack J, Cho YL, Garrett L, Hölter SM, Irmler M, Kistler M, Kraiger M, Mayer-Kuckuk P, Moreth K, Rathkolb B, Rozman J, da Silva Buttkus P, Treise I, Zimprich A, Gampe K, Hutterer C, Stöger C, Leuchtenberger S, Maier H, Miller M, Scheideler A, Wu M, Beckers J, Bekeredjian R, Brielmeier M, Busch DH, Klingenspor M, Klopstock T, Ollert M, Schmidt-Weber C, Stöger T, Wolf E, Wurst W, Yildirim AÖ, Zimmer A, Gailus-Durner V, and Hrabě de Angelis M

Subjects
Animals, Humans, Disease Models, Animal, Mice, Transgenic, Phenotype
Abstract

Since decades, model organisms have provided an important approach for understanding the mechanistic basis of human diseases. The German Mouse Clinic (GMC) was the first phenotyping facility that established a collaboration-based platform for phenotype characterization of mouse lines. In order to address individual projects by a tailor-made phenotyping strategy, the GMC advanced in developing a series of pipelines with tests for the analysis of specific disease areas. For a general broad analysis, there is a screening pipeline that covers the key parameters for the most relevant disease areas. For hypothesis-driven phenotypic analyses, there are thirteen additional pipelines with focus on neurological and behavioral disorders, metabolic dysfunction, respiratory system malfunctions, immune-system disorders and imaging techniques. In this article, we give an overview of the pipelines and describe the scientific rationale behind the different test combinations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Published
2018
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2. The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations.

Author

Fuchs H, Sabrautzki S, Przemeck GK, Leuchtenberger S, Lorenz-Depiereux B, Becker L, Rathkolb B, Horsch M, Garrett L, Östereicher MA, Hans W, Abe K, Sagawa N, Rozman J, Vargas-Panesso IL, Sandholzer M, Lisse TS, Adler T, Aguilar-Pimentel JA, Calzada-Wack J, Ehrhard N, Elvert R, Gau C, Hölter SM, Micklich K, Moreth K, Prehn C, Puk O, Racz I, Stoeger C, Vernaleken A, Michel D, Diener S, Wieland T, Adamski J, Bekeredjian R, Busch DH, Favor J, Graw J, Klingenspor M, Lengger C, Maier H, Neff F, Ollert M, Stoeger T, Yildirim AÖ, Strom TM, Zimmer A, Wolf E, Wurst W, Klopstock T, Beckers J, Gailus-Durner V, and Hrabé de Angelis M

Subjects
Animals, Bone and Bones metabolism, Calcium-Binding Proteins, Chromosome Mapping, Disease Models, Animal, Energy Metabolism genetics, Exome, Female, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Kidney metabolism, Kidney physiopathology, Kidney Function Tests, Male, Mice, Mice, Knockout, Osteitis Deformans genetics, Osteitis Deformans metabolism, Osteitis Deformans pathology, Skeleton abnormalities, Genetic Association Studies, Glycoproteins genetics, Mutation, Phenotype
Abstract

The vertebrate Scube (Signal peptide, CUB, and EGF-like domain-containing protein) family consists of three independent members, Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Limited information about the general function of this gene family is available, and their roles during adulthood. Here, we present the first Scube3 mutant mouse line (Scube3 N294K/N294K ), which clearly shows phenotypic alterations by carrying a missense mutation in exon 8, and thus contributes to our understanding of SCUBE3 functions. We performed a detailed phenotypic characterization in the German Mouse Clinic (GMC). Scube3 N294K/N294K mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function, and hearing impairments. These findings correlate with characteristics of the rare metabolic bone disorder Paget disease of bone (PDB), associated with the chromosomal region of human SCUBE3 In addition, alterations in energy metabolism, behavior, and neurological functions were detected in Scube3 N294K/N294K mice. The Scube3 N294K/N294K mutant mouse line may serve as a new model for further studying the effect of impaired SCUBE3 gene function., (Copyright © 2016 Fuchs et al.)

Published
2016
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3. 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, Osteoporosis, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, 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

4. 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, Human Genome, Nutrition, 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

5. Viable Ednra Y129F mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation

Author

Ali Önder Yildirim, Valerie Gailus-Durner, Tim M. Strom, Susan Marschall, Michael A. Sandholzer, Wolfgang Wurst, Katharina Baron, Sibylle Sabrautzki, Eckhard Wolf, Martin Hrabě de Angelis, Jan Rozman, Robert Brommage, Claudia Stoeger, Birgit Rathkolb, Lillian Garrett, Sabine Hoelter, Christine Gau, Leuchtenberger Stefanie, Ingrid L. Vargas Panesso, Christoph Lengger, Martin Klingenspor, Lore Becker, Thomas Klopstock, Helmut Fuchs, Bettina Lorenz-Depiereux, Gerhard K. H. Przemeck, Alexandra Vernaleken, and Wolfgang Hans

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Genotype, Mutant, physiopathology [Mandibulofacial Dysostosis], genetics [Mandibulofacial Dysostosis], Mutagenesis (molecular biology technique), 030105 genetics & heredity, Biology, medicine.disease_cause, Article, genetics [Receptor, Endothelin A], Mice, 03 medical and health sciences, ddc:570, Genetics, medicine, Animals, Humans, Craniofacial, genetics [Alopecia], Mutation, physiopathology [Alopecia], Alopecia, Receptor, Endothelin A, medicine.disease, Endothelin 1, Phenotype, Human genetics, 030104 developmental biology, Dysplasia, Mandibulofacial Dysostosis, Signal Transduction
Abstract

Animal models resembling human mutations are valuable tools to research the features of complex human craniofacial syndromes. This is the first report on a viable dominant mouse model carrying a non-synonymous sequence variation within the endothelin receptor type A gene (Ednra c.386A>T, p.Tyr129Phe) derived by an ENU mutagenesis program. The identical amino acid substitution was reported recently as disease causing in three individuals with the mandibulofacial dysostosis with alopecia (MFDA, OMIM 616367) syndrome. We performed standardized phenotyping of wild-type, heterozygous, and homozygous Ednra Y129F mice within the German Mouse Clinic. Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals. As observed in MFDA-affected individuals, mutant Ednra Y129F mice exhibit hearing impairment in line with strong abnormalities of the ossicles and further, reduction of some lung volumetric parameters. In general, heterozygous and homozygous mice demonstrated inter-individual diversity of expression of the craniofacial phenotypes as observed in MFDA patients but without showing any cleft palates, eyelid defects, or alopecia. Mutant Ednra Y129F mice represent a valuable viable model for complex human syndromes of the first and second pharyngeal arches and for further studies and analysis of impaired endothelin 1 (EDN1)–endothelin receptor type A (EDNRA) signaling. Above all, Ednra Y129F mice model the recently published human MFDA syndrome and may be helpful for further disease understanding and development of therapeutic interventions. Electronic supplementary material The online version of this article (doi:10.1007/s00335-016-9664-5) contains supplementary material, which is available to authorized users.

Published
2016
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6. Streptozotocin-induced β-cell damage, high fat diet, and metformin administration regulate Hes3 expression in the adult mouse brain

Author

Nikolakopoulou, Polyxeni, Chatzigeorgiou, Antonios, Consortium, German Mouse Clinic, Wolf, Eckhard, Klingenspor, Martin, Ollert, Markus, Schmidt-Weber, Carsten, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, Tsata, Vasiliki, Monasor, Laura Sebastian, Kourtzelis, Ioannis, Troullinaki, Maria, Witt, Anke, Anastasiou, Vivian, Chrousos, George, Yi, Chun-Xia, García-Cáceres, Cristina, Tschöp, Matthias H, Bornstein, Stefan R, Androutsellis-Theotokis, Andreas, Becker, Lore, Toutouna, Louiza, Klopstock, Thomas, Treise, Irina, Busch, Dirk H, Beckers, Johannes, Moreth, Kristin, Bekeredjian, Raffi, Garrett, Lillian, Hölter, Sabine M, Zimprich, Annemarie, Wurst, Wolfgang, Masjkur, Jimmy, Brommage, Robert, Amarie, Oana, Graw, Jochen, Calzada-Wack, Julia, Neff, Frauke, Zimmer, Andreas, Östereicher, Manuela, Steinkamp, Ralph, Lengger, Christoph, Maier, Holger, Arps-Forker, Carina, Stoeger, Claudia, Leuchtenberger, Stefanie, Poser, Steven W, Rozman, Jan, Rathkolb, Birgit, Aguilar-Pimentel, Juan Antonio, University of Zurich, Androutsellis-Theotokis, Andreas, APH - Aging & Later Life, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Laboratory for Endocrinology, AGEM - Endocrinology, metabolism and nutrition, and ACS - Diabetes & metabolism

Subjects
Male, 0301 basic medicine, Aging, medicine.medical_treatment, 10265 Clinic for Endocrinology and Diabetology, lcsh:Medicine, drug effects [Gene Expression Regulation], Type 2 diabetes, Insulin-Secreting Cells, pathology [Insulin-Secreting Cells], Basic Helix-Loop-Helix Transcription Factors, Medicine, lcsh:Science, genetics [Nerve Tissue Proteins], Multidisciplinary, Brain, toxicity [Streptozocin], Metformin, Phenotype, Hes3 protein, mouse, medicine.drug, medicine.medical_specialty, genetics [Basic Helix-Loop-Helix Transcription Factors], Nerve Tissue Proteins, 610 Medicine & health, Diet, High-Fat, Article, Streptozocin, 03 medical and health sciences, Insulin resistance, Diabetes mellitus, Internal medicine, Animals, metabolism [Aging], Progenitor cell, 1000 Multidisciplinary, Type 1 diabetes, metabolism [Nerve Tissue Proteins], deficiency [Nerve Tissue Proteins], business.industry, Insulin, lcsh:R, administration & dosage [Metformin], metabolism [Insulin-Secreting Cells], medicine.disease, Streptozotocin, Repressor Proteins, Mice, Inbred C57BL, metabolism [Basic Helix-Loop-Helix Transcription Factors], 030104 developmental biology, Endocrinology, Gene Expression Regulation, deficiency [Basic Helix-Loop-Helix Transcription Factors], metabolism [Brain], lcsh:Q, business, ddc:600, drug effects [Insulin-Secreting Cells]
Abstract

Diabetes mellitus is a group of disorders characterized by prolonged high levels of circulating blood glucose. Type 1 diabetes is caused by decreased insulin production in the pancreas whereas type 2 diabetes may develop due to obesity and lack of exercise; it begins with insulin resistance whereby cells fail to respond properly to insulin and it may also progress to decreased insulin levels. The brain is an important target for insulin, and there is great interest in understanding how diabetes affects the brain. In addition to the direct effects of insulin on the brain, diabetes may also impact the brain through modulation of the inflammatory system. Here we investigate how perturbation of circulating insulin levels affects the expression of Hes3, a transcription factor expressed in neural stem and progenitor cells that is involved in tissue regeneration. Our data show that streptozotocin-induced β-cell damage, high fat diet, as well as metformin, a common type 2 diabetes medication, regulate Hes3 levels in the brain. This work suggests that Hes3 is a valuable biomarker helping to monitor the state of endogenous neural stem and progenitor cells in the context of diabetes mellitus.

Published
2018
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7. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Author

Bowl, Michael R., Simon, Michelle M., Ingham, Neil J., Greenaway, Simon, Santos, Luis, Cater, Heather, Taylor, Sarah, Mason, Jeremy, Kurbatova, Natalja, Pearson, Selina, Bower, Lynette R., Clary, Dave A., Meziane, Hamid, Reilly, Patrick, Minowa, Osamu, Kelsey, Lois, Allen, Sue, Clementson-Mobbs, Sharon, Codner, Gemma, Fray, Martin, Gardiner, Wendy, Joynson, Russell, Kenyon, Janet, Loeffler, Jorik, Nell, Barbara, Parker, Andrew, Quwailid, Deen, Stewart, Michelle, Walling, Alison, Zaman, Rumana, Chen, Chao Kung, Conte, Nathalie, Matthews, Peter, Relac, Mike, Tudose, Ilinca, Warren, Jonathan, Le Marchand, Elise, El Amri, Amal, El Fertak, Leila, Ennah, Hamid, Ali-Hadji, Dalila, Ayadi, Abdel, Wattenhofer-Donze, Marie, Moulaert, David, Jacquot, Sylvie, André, Philippe, Birling, Marie Christine, Pavlovic, Guillaume, Lalanne, Valérie, Lux, Aline, Riet, Fabrice, Mittelhaeuser, Christophe, Bour, Raphael, Guimond, Alain, Bam'Hamed, Chaouki, Leblanc, Sophie, Vasseur, Laurent, Selloum, Mohammed, Sorg, Tania, Ayabe, Shinya, Furuse, Tamio, Kaneda, Hideki, Kobayashi, Kimio, Masuya, Hiroshi, Miura, Ikuo, Obata, Yuichi, Suzuki, Tomohiro, Tamura, Masaru, Tanaka, Nobuhiko, Yamada, Ikuko, Yoshiki, Atsushi, Berberovic, Zorana, Bubshait, Mohammed, Cabezas, Jorge, Carroll, Tracy, Clark, Greg, Clarke, Shannon, Creighton, Amie, Danisment, Ozge, Eskandarian, Mohammad, Feugas, Patricia, Gertsenstein, Marina, Guo, Ruolin, Hunter, Jane, Jacob, Elsa, Lan, Qing, Laurin, Valerie, Law, Napoleon, MacMaster, Sue, Miller, David, Morikawa, Lily, Newbigging, Susan, Owen, Celeste, Penton, Patricia, Pereira, Monica, Qu, Dawei, Shang, Xueyuan, Sleep, Gillian, Sohel, Khondoker, Tondat, Sandra, Wang, Yanchun, Vukobradovic, Igor, Zhu, Yingchun, Chiani, Francesco, Di Pietro, Chiara, Di Segni, Gianfranco, Ermakova, Olga, Ferrara, Filomena, Fruscoloni, Paolo, Gambadoro, Aalessia, Gastaldi, Serena, Golini, Elisabetta, Sala, Gina La, Mandillo, Silvia, Marazziti, Daniela, Massimi, Marzia, Matteoni, Rafaele, Orsini, Tiziana, Pasquini, Miriam, Raspa, Marcello, Rauch, Aline, Rossi, Gianfranco, Rossi, Nicoletta, Putti, Sabrina, Scavizzi, Ferdinando, Tocchini-Valentini, Giuseppe D., Beig, Joachim, Bürger, Antje, Giesert, Florian, Graw, Jochen, Kühn, Ralf, Oritz, Oskar, Schick, Joel, Seisenberger, Claudia, Amarie, Oana, Garrett, Lillian, Hölter, Sabine M., Zimprich, Annemarie, Aguilar-Pimentel, Antonio, Beckers, Johannes, Brommage, Robert, Calzada-Wack, Julia, Fuchs, Helmut, Gailus-Durner, Valérie, Lengger, Christoph, Leuchtenberger, Stefanie, Maier, Holger, Marschall, Susan, Moreth, Kristin, Neff, Frauke, Östereicher, Manuela A., Rozman, Jan, Steinkamp, Ralph, Stoeger, Claudia, Treise, Irina, Stoeger, Tobias, Yildrim, Ali Önder, Eickelberg, Oliver, Becker, Lore, Klopstock, Thomas, Ollert, Markus, Busch, Dirk H., Schmidt-Weber, Carsten, Bekeredjian, Raffi, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Klingenspor, Martin, Tocchini-Valentini, Glauco P., Gao, Xiang, Bradley, Allan, Skarnes, William C., Moore, Mark, Beaudet, Arthur L., Justice, Monica J., Seavitt, John, Dickinson, Mary E., Wurst, Wolfgang, De Angelis, Martin Hrabe, Herault, Yann, Wakana, Shigeharu, Nutter, Lauryl M.J., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Svenson, Karen L., Braun, Robert E., West, David B., Lloyd, K. C.Kent, Adams, David J., White, Jacqui, Karp, Natasha, Flicek, Paul, Smedley, Damian, Meehan, Terrence F., Parkinson, Helen E., Teboul, Lydia M., Wells, Sara, Steel, Karen P., Mallon, Ann Marie, Brown, Steve D.M., Mason, Jeremy [0000-0002-2796-5123], de Angelis, Martin Hrabe [0000-0002-7898-2353], Herault, Yann [0000-0001-7049-6900], Wakana, Shigeharu [0000-0001-8532-0924], McKerlie, Colin [0000-0002-2232-0967], Lloyd, KC Kent [0000-0002-5318-4144], Flicek, Paul [0000-0002-3897-7955], Smedley, Damian [0000-0002-5836-9850], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Cancer Research, Candidate gene, General Physics and Astronomy, Datasets as Topic, Mice, 2.1 Biological and endogenous factors, Protein Interaction Maps, Aetiology, lcsh:Science, Pediatric, Genetics, Mice, Knockout, Multidisciplinary, medicine.diagnostic_test, Hearing Tests, Ear, Phenotype, medicine.anatomical_structure, Technology Platforms, International Mouse Phenotyping Consortium, medicine.symptom, Biotechnology, Hearing Loss/epidemiology, Hearing loss, Knockout, 1.1 Normal biological development and functioning, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Clinical Research, Underpinning research, medicine, otorhinolaryngologic diseases, Auditory system, Animals, Genetic Testing, IMPC, mouse, auditory dysfunction, Set (psychology), Hearing Loss, Gene, Genetic testing, Auditory dysfunction, Human Genome, General Chemistry, 030104 developmental biology, Protein Interaction Maps/genetics, lcsh:Q
Abstract

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function., The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Published
2017
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8. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Author

Paul Flicek, Raffaele Teperino, Lydia Teboul, Thomas Werner, Marie-France Champy, Christopher J. Lelliott, Graham R. Williams, Jacqueline K. White, Gregor Miller, Mary E. Dickinson, Ann M Flenniken, Radislav Sedlacek, Martin Hrabé de Angelis, John R. Seavitt, Peter I. Croucher, Maria del Mar Muniz Moreno, Sara Wells, Jan Rozman, Terrence F. Meehan, Kristian F Odfalk, Juan Gallegos, J. H. Duncan Bassett, Mohammed Selloum, John G. Logan, Sylvie Jacquot, Elena J. Ghirardello, Robert Braun, Frantisek Spoutil, Kevin C K Lloyd, Lore Becker, Stephen A. Murray, Jan Prochazka, Elif F. Acar, Taylor S Vales, Michelle Simon, Helmut Fuchs, Nadine Spielmann, Mark Griffiths, Piia Keskivali-Bond, Valerie Gailus-Durner, Tania Sorg, Christine Schütt, Jeremy Mason, Helen Parkinson, Karen L. Svenson, Abdel Ayadi, Anna L Swan, Jason D. Heaney, Colin McKerlie, Wolfgang Wurst, Ann-Marie Mallon, Heather Cater, Stefanie Leuchtenberger, Harald Grallert, Steve D.M. Brown, Stefan Brandmaier, Yann Herault, Philipp Mayer-Kuckuk, Corey L. Reynolds, Ala Moshiri, Robert Brommage, Derek D. Cissell, Lauryl M J Nutter, Connor Lally, MRC Harwell Institute [UK], German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Helmholtz-Zentrum München (HZM), The Wellcome Trust Sanger Institute [Cambridge], University of Michigan [Ann Arbor], University of Michigan System, University of California [Davis] (UC Davis), University of California, Baylor College of Medicine (BCM), Baylor University, European Molecular Biology Laboratory [Hinxton], University of Toronto, University of Manitoba [Winnipeg], Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], French National Infrastructure for Mouse Phenogenomics (PHENOMIN), The Jackson Laboratory [Bar Harbor] (JAX), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Imperial College London, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Garvan Institute of Medical Research [Sydney, Australia], St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Université de Nouvelle-Galles du Sud - UNSW [Sydney, Australia], Mundlos, Stefan, Wellcome Trust, Commission of the European Communities, European Commission, Herault, Yann, Helmholtz Zentrum München = German Research Center for Environmental Health, University of California (UC), Garvan Institute of medical research, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Technische Universität München [München] (TUM), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Swan, Anna L [0000-0003-1810-3756], Rozman, Jan [0000-0002-8035-8904], Del Mar Muñiz Moreno, Maria [0000-0002-2662-890X], Leuchtenberger, Stefanie [0000-0003-2475-0810], Brommage, Robert [0000-0002-9947-3822], Grallert, Harald [0000-0002-6876-9655], Werner, Thomas [0000-0003-0402-4539], Teperino, Raffaele [0000-0001-8815-1409], Becker, Lore [0000-0002-6890-4984], Miller, Gregor [0000-0002-4281-4905], Seavitt, John R [0000-0003-3209-3187], Cissell, Derek D [0000-0002-6450-422X], Acar, Elif F [0000-0003-2908-7691], Lelliott, Christopher J [0000-0001-8087-4530], Braun, Robert E [0000-0003-3856-9465], Cater, Heather [0000-0002-8696-6070], Flicek, Paul [0000-0002-3897-7955], Ghirardello, Elena J [0000-0002-1100-9217], Heaney, Jason D [0000-0001-8475-8828], Lally, Connor [0000-0002-3801-1966], Logan, John G [0000-0003-2801-700X], Mason, Jeremy [0000-0002-2796-5123], Nutter, Lauryl MJ [0000-0001-9619-146X], Odfalk, Kristian F [0000-0003-4152-4583], Prochazka, Jan [0000-0003-4675-8995], Selloum, Mohammed [0000-0003-4057-3519], Spoutil, Frantisek [0000-0002-7310-3487], Svenson, Karen L [0000-0002-7928-1911], Vales, Taylor S [0000-0001-9751-5681], Wells, Sara E [0000-0002-0572-0600], White, Jacqueline K [0000-0001-6268-2826], Sedlacek, Radislav [0000-0002-3352-392X], Wurst, Wolfgang [0000-0003-4422-7410], Lloyd, KC Kent [0000-0002-5318-4144], Williams, Graham R [0000-0002-8555-8219], Herault, Yann [0000-0001-7049-6900], Brown, Steve DM [0000-0002-0617-4824], Hrabe de Angelis, Martin [0000-0002-7898-2353], and Apollo - University of Cambridge Repository

Subjects
Male, Osteoporosis, genetics [Gene Expression Regulation], Transgenic, Transcriptome, Mice, 0302 clinical medicine, Animal Cells, Aetiology, Musculoskeletal System, Connective Tissue Cells, Genetics & Heredity, 0303 health sciences, Genomics, 3. Good health, Cellular Types, musculoskeletal diseases, Genotype, In silico, 1.1 Normal biological development and functioning, 03 medical and health sciences, genetics [Osteoporosis], Rheumatology, pathology [Osteoblasts], Genetic, Genome-Wide Association Studies, Genetics, GENOME-WIDE ASSOCIATION, Molecular Biology, Skeleton, Ecology, Evolution, Behavior and Systematics, METAANALYSIS, metabolism [Osteoblasts], 0604 Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Osteoblasts, IDENTIFICATION, Biology and Life Sciences, Computational Biology, medicine.disease, COLLAGEN, Biological Tissue, OSTEOGENESIS IMPERFECTA, DISCOVERY, IMPC Consortium, Mutation, Animal Studies, Developmental Biology, Candidate gene, Cancer Research, Bone density, Gene Expression, Osteoclasts, [SDV.GEN] Life Sciences [q-bio]/Genetics, QH426-470, Bone remodeling, Bone Density, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Protein Interaction Maps, Connective Tissue Diseases, Promoter Regions, Genetic, Genetics (clinical), Bone mineral, Sex Characteristics, genetics [Bone Density], metabolism [Osteoclasts], Genetic Pleiotropy, Animal Models, pathology [Osteoclasts], Phenotype, DIFFERENTIATION, Experimental Organism Systems, ANIMAL-MODELS, Connective Tissue, SEX, Female, Anatomy, Technology Platforms, Life Sciences & Biomedicine, Research Article, metabolism [Osteoporosis], Mouse Models, 030209 endocrinology & metabolism, Mice, Transgenic, Biology, Research and Analysis Methods, Promoter Regions, Model Organisms, Underpinning research, medicine, Animals, ddc:610, Bone, 030304 developmental biology, Human Genetics, Cell Biology, Genome Analysis, Gene Ontology, Gene Expression Regulation, Musculoskeletal, Genome-Wide Association Study
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., Author summary Patients affected by osteoporosis frequently present with decreased BMD and increased fracture risk. Genes are known to control the onset and progression of bone diseases such as osteoporosis. Therefore, we aimed to identify osteoporosis-related genes using BMD measures obtained from a large pool of mutant mice genetically modified for deletion of individual genes (knockout mice). In a collaborative endeavor involving several research sites world-wide, we generated and phenotyped 3,823 knockout mice and identified 200 genes which regulated BMD. Of the 200 BMD genes, 141 genes were previously not known to affect BMD. The discovery and study of novel BMD genes will help to better understand the causes and therapeutic options for patients with low BMD. In the long run, this will improve the clinical management of osteoporosis.

Published
2021
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