Molecular Metabolism (Dec 2022)
Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome
- 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
Affiliations
- Gandhari Maity-Kumar
- Institute 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, Germany
- Lisa Ständer
- Institute for Diabetes and Obesity, Helmholtz München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
- Meri DeAngelis
- Institute 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, Germany
- Sooyeon Lee
- Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
- Anna Molenaar
- Institute for Diabetes and Obesity, Helmholtz München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Research Unit NeuroBiology of Diabetes, Helmholtz München, Neuherberg, Germany
- Lore Becker
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, Germany
- Lillian Garrett
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
- Oana V. Amerie
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, Germany
- Sabine M. Hoelter
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
- Wolfgang Wurst
- Chair 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, Germany
- Helmut Fuchs
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, Germany
- Annette Feuchtinger
- Research Unit Analytical Pathology, Helmholtz München, Neuherberg, Germany
- Valerie Gailus-Durner
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz München, German Research Center for Environmental Health, Neuherberg, Germany
- Cristina Garcia-Caceres
- Institute 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, Germany
- Ahmed E. Othman
- Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, 52074 Aachen, Germany
- Caroline Brockmann
- Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, 52074 Aachen, Germany
- Vanessa I. Schöffling
- Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, 52074 Aachen, Germany
- Katja Beiser
- Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, 52074 Aachen, Germany
- Heiko Krude
- Institute of Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, Germany
- Piotr A. Mroz
- Department of Chemistry, Indiana University, Bloomington, IN, USA
- Susanna Hofmann
- German 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, Germany
- Jan Tuckermann
- Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
- Richard D. DiMarchi
- Department of Chemistry, Indiana University, Bloomington, IN, USA
- Martin Hrabe de Angelis
- German 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, Germany
- Matthias H. Tschöp
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Helmholtz München, München, Germany
- Paul T. Pfluger
- Institute 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, Germany
- Timo D. Müller
- Institute 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.
- Journal volume & issue
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Vol. 66
p. 101616
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.
