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

Mol Metab. 2022 Dec:66:101616. doi: 10.1016/j.molmet.2022.101616. Epub 2022 Oct 18.

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.

Keywords: Allan-Herndon Dudley Syndrome; Energy metabolism; Mct8; Motor coordination; Myelination; Oatp1c1; Thyroid hormone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Mental Retardation, X-Linked* / genetics
  • Mice
  • Monocarboxylic Acid Transporters / genetics
  • Symporters* / genetics
  • Thyroid Hormones

Substances

  • Monocarboxylic Acid Transporters
  • Symporters
  • Thyroid Hormones

Supplementary concepts

  • Allan-Herndon-Dudley syndrome