Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877822001855 |
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| 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 Timo D. Müller |
| author_facet | 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 Timo D. Müller |
| author_sort | Gandhari Maity-Kumar |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T01:17:01Z |
| format | Article |
| id | doaj.art-d20220d136ff4111b5354c35a970afe0 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-12T01:17:01Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-d20220d136ff4111b5354c35a970afe02022-12-22T03:53:55ZengElsevierMolecular Metabolism2212-87782022-12-0166101616Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley SyndromeGandhari Maity-Kumar0Lisa Ständer1Meri DeAngelis2Sooyeon Lee3Anna Molenaar4Lore Becker5Lillian Garrett6Oana V. Amerie7Sabine M. Hoelter8Wolfgang Wurst9Helmut Fuchs10Annette Feuchtinger11Valerie Gailus-Durner12Cristina Garcia-Caceres13Ahmed E. Othman14Caroline Brockmann15Vanessa I. Schöffling16Katja Beiser17Heiko Krude18Piotr A. Mroz19Susanna Hofmann20Jan Tuckermann21Richard D. DiMarchi22Martin Hrabe de Angelis23Matthias H. Tschöp24Paul T. Pfluger25Timo D. Müller26Institute for Diabetes and Obesity, Helmholtz München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, München, GermanyInstitute for Diabetes and Obesity, Helmholtz München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, GermanyInstitute for Diabetes and Obesity, Helmholtz München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Comparative Molecular Endocrinology, University of Ulm, Ulm, GermanyInstitute for Diabetes and Obesity, Helmholtz München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Research Unit NeuroBiology of Diabetes, Helmholtz München, Neuherberg, GermanyInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, GermanyInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, GermanyChair of Developmental Genetics, TUM School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany; Deutsches Institut für Neurodegenerative Erkrankungen (DZNE) Site Munich, Feodor-Lynen-Str. 17, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 17, 81377 Munich, GermanyInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, GermanyResearch Unit Analytical Pathology, Helmholtz München, Neuherberg, GermanyInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute for Diabetes and Obesity, Helmholtz München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Medizinische Klinik and Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, GermanyDepartment of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, 52074 Aachen, GermanyDepartment of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, 52074 Aachen, GermanyDepartment of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, 52074 Aachen, GermanyDepartment of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, 52074 Aachen, GermanyInstitute of Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, GermanyDepartment of Chemistry, Indiana University, Bloomington, IN, USAGerman Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Diabetes and Regeneration Research, Helmholtz München, Neuherberg, GermanyInstitute of Comparative Molecular Endocrinology, University of Ulm, Ulm, GermanyDepartment of Chemistry, Indiana University, Bloomington, IN, USAGerman Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, Germany; Chair of Experimental Genetics, TUM School of Life Sciences, Technische Universität München, Freising, GermanyGerman Center for Diabetes Research (DZD), Neuherberg, Germany; Helmholtz München, München, GermanyInstitute for Diabetes and Obesity, Helmholtz München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Neurobiology of Diabetes, Department of Medicine, Technische Universität München, München, GermanyInstitute for Diabetes and Obesity, Helmholtz München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Corresponding author. Institute for Diabetes and Obesity, Helmholtz München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.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.http://www.sciencedirect.com/science/article/pii/S2212877822001855Allan-Herndon Dudley SyndromeThyroid hormoneMct8Oatp1c1Energy metabolismMyelination |
| spellingShingle | 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 Timo D. Müller Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome Molecular Metabolism Allan-Herndon Dudley Syndrome Thyroid hormone Mct8 Oatp1c1 Energy metabolism Myelination |
| title | Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome |
| title_full | Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome |
| title_fullStr | Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome |
| title_full_unstemmed | Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome |
| title_short | Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome |
| title_sort | validation of mct8 oatp1c1 dko mice as a model organism for the allan herndon dudley syndrome |
| topic | Allan-Herndon Dudley Syndrome Thyroid hormone Mct8 Oatp1c1 Energy metabolism Myelination |
| url | http://www.sciencedirect.com/science/article/pii/S2212877822001855 |
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