Journal Article

DZNE-2022-01672

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome.

Maity-Kumar, G. ; Ständer, L. ; DeAngelis, M. ; Lee, S. ; Molenaar, A. ; Becker, L. ; Garrett, L. ; Amerie, O. V. ; Hoelter, S. M. ; Wurst, W.DZNE* ; Fuchs, H. ; Feuchtinger, A. ; Gailus-Durner, V. ; Garcia-Caceres, C. ; Othman, A. E. ; Brockmann, C. ; Schöffling, V. I. ; Beiser, K. ; Krude, H. ; Mroz, P. A. ; Hofmann, S. ; Tuckermann, J. ; DiMarchi, R. D. ; Hrabe de Angelis, M. ; Tschöp, M. H. ; Pfluger, P. T. ; Müller, T. D. (Corresponding author)

2022
Elsevier Oxford [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.molmet.2022.101616

Abstract: 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.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.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.We conclude that Mct8/Oatp1c1 dKO mice are a valuable model organism for the preclinical evaluation of drugs designed to treat the AHDS.

Keyword(s): Animals (MeSH) ; Mice (MeSH) ; Monocarboxylic Acid Transporters: genetics (MeSH) ; Symporters: genetics (MeSH) ; Mental Retardation, X-Linked: genetics (MeSH) ; Thyroid Hormones (MeSH) ; Allan-Herndon Dudley Syndrome ; Energy metabolism ; Mct8 ; Motor coordination ; Myelination ; Oatp1c1 ; Thyroid hormone

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Contributing Institute(s):

1. Genome Engineering (AG Wurst)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2022

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