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Updated: Feb 17, 2026
Generation of a Mouse Spontaneous Autoimmune Thyroiditis Model
Published on: March 17, 2023
CRISPR/Cas9 Editing of the Mouse Thra Gene Produces Models with Variable Resistance to Thyroid Hormone
Suzy Markossian1, Romain Guyot1, Sabine Richard1
11 Institut de Génomique Fonctionnelle de Lyon, Université de Lyon CNRS UMR 5242, INRA USC 1370, Ecole Normale Supérieure de Lyon , Lyon, France .
Background:
Resistance to thyroid hormone due to THRA mutations (RTHα) is a recently discovered genetic disease, displaying important variability in its clinical presentation. The mutations alter the function of TRα1, one of the two nuclear receptors for thyroid hormone.
Methods:
The aim of this study was to understand the relationship between specific THRA mutations and phenotype. CRISPR/Cas9 genome editing was used to generate five new mouse models of RTHα, with frameshift or missense mutations.
Results:
Like human patients, mutant mice displayed a hypothyroid-like phenotype, with altered development. Phenotype severity varied between the different mouse models, mainly depending on the ability of the mutant receptor to interact with transcription corepressor in the presence of thyroid hormone.
Conclusion:
The present mutant mice represent highly relevant models for the human genetic disease which will be useful for future investigations.
Insights
New mouse models reveal how thyroid hormone receptor alpha (TRα) mutations cause resistance to thyroid hormone (RTHα), impacting development. Phenotype severity correlates with mutant receptor interactions, aiding future RTHα research.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Resistance to thyroid hormone alpha (RTHα) is a genetic disorder caused by mutations in the THRA gene.
- These mutations affect the function of the thyroid hormone receptor alpha 1 (TRα1), a key nuclear receptor involved in thyroid hormone action.
Purpose of the Study:
- To investigate the genotype-phenotype relationship in RTHα.
- To develop and characterize novel mouse models for studying RTHα.
Main Methods:
- Utilized CRISPR/Cas9 genome editing to create five distinct mouse models of RTHα.
- Generated mouse models with frameshift or missense mutations in the THRA gene.
Main Results:
- Mutant mice exhibited a hypothyroid-like phenotype and developmental alterations, mirroring human RTHα patients.
- The severity of the observed phenotype varied among the mouse models.
- Phenotype severity was linked to the mutant TRα1 receptor's ability to interact with transcription corepressors in a thyroid hormone-dependent manner.
Conclusions:
- The developed mouse models are highly relevant for studying human RTHα.
- These models will facilitate future research into the mechanisms and potential treatments for RTHα.
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