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Endocrine Abstracts (2024) 101 OP02-05 | DOI: 10.1530/endoabs.101.OP-02-05

ETA2024 Oral Presentations Oral Session 2: Thyroid hormone action in the brain (5 abstracts)

A Novel MCT8 point-mutant mouse model shows effectiveness of phenylbutyrate treatment

Doreen Braun 1 , Niklas Sonntag 2 , Mandy Gueth-Steffen 2 , Esther Dall 2 & Ulrich Schweizer 3


1Rheinsiche Friedrich-Wilhelms, Universität Bonn, Bonn, Germany; 2Rheinische Friedrich-Wilhelms Universität Bonn, Institut für Biochemie und Molekularbiologie, Bonn, Germany; 3Rheinische Friedrich-Wilhelms-Uni, Institut für Biochemie und Mol. Bio, Universitätsklinikum Bonn, Bonn, Germany


Objectives: Pathogenic variants in monocarboxylate transporter 8 (MCT8, SLC16A2) cause motor and intellectual disability and movement disorder (Allan-Herndon-Dudley Syndrome, AHDS). The mutation affects the transport of thyroid hormones across plasma membranes, including the blood-brain-barrier. While knockout mouse models for Mct8 have allowed important insights into the physiological function of Mct8, most patients are carrying pathogenic missense variants. Recently, an “avatar” mouse model was described, which is carrying the pathogenic P321L variant. These mice replicate several characteristics of AHDS patients without the need of additional mutation of Oatp1c1 or Dio2. Here, we describe the generation and characterization of a novel Mct8 L223R mouse model, which we aim to treat with phenylbutyrate.

Methods: We have generated a mouse model carrying the L223R mutation in the mouse Mct8 gene (L291R in human). Western blots and deiodinase activity assays were performed in liver, kidney, and brain. Thyroid hormone uptake assays were performed in primary astrocytes treated or not with phenylbutyrate.

Results: Western blots revealed elevated expression of Mct8 in kidney and liver. Elevated deiodinase activities in liver, kidney, and brain support the pathogenicity of the mutant protein in mice - similar as described for Mct8-KO mice. In the brain, the number of PV-expressing interneurons was reduced at 28 days in the primary somatosensory cortex. Primary astrocytes showed diminished T3 uptake compared to controls. Treatment with phenylbutyrate greatly increased TH uptake in Mct8 L233R astrocytes.

Conclusion: We present a novel Mct8-mutated mouse model which recapitulates key features of the disease. Most importantly, phenylbutyrate treatment restored TH uptake into primary astrocytes.

Volume 101

46th Annual Meeting of the European Thyroid Association (ETA) 2024

European Thyroid Association 

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