Endocrine Abstracts

Resistance to thyroid hormone due to THRA mutations (RTHα) is a recently discovered genetic disease with high variability in its clinical presentation. This variability may result from the fact that patients bear different types of mutations, which may impact in different ways the functionality of thyroid hormone receptor α1 (TRα1). Our aim was to understand the relationship between specific THRA mutations and symptoms, using mouse models. CRISPR/Cas9 genome editing was used to generate five new models of RTHα, the human genetic disease caused by mutations in THRA. Like human patients, the mutant mice displayed a hypothyroid-like phenotype, with altered post-natal development. Phenotype severity varied over a broad range between models, mainly depending on the ability of the mutant receptor to interact with the NcoR transcription corepressor in the presence of thyroid hormone. These data illustrate the outstanding possibilities offered by CRISPR/Cas9 genome editing which allows to rapidly produce mouse models of human genetic disease, and even to model individual sporadic cases of the disease.