FVB But Not B6 Mice Carrying the Thr92Ala-Dio2 Polymorphism Have Impaired Thyroid Hormonogenesis and Goiter

The Thr92Ala-Dio2 polymorphism is prevalent worldwide, with about 50% of the population carrying at least 1 allele. The Ala92-Dio2 allele encodes a less active type 2 deiodinase enzyme and has been associated with neurodegenerative diseases, hypertension, and insulin resistance. To understand why its phenotypic effects are variable across different populations, in this study we examined the impact of genetic background on the Thr92Ala-Dio2 polymorphism. We focused on the thyroid gland of 2 genetically distant mouse strains, the C57BL/6J (B6) and the FVB/N (FVB). While the B6-Ala92-Dio2 mice have no meaningful phenotype, the FVB-Ala92-Dio2 exhibit a goiter (about 2.3-fold heavier thyroid) with an about 1.7-fold enlarged thyroid follicular area and impaired hormonogenesis with reduced thyroglobulin content of T4 and T3, 35% to 50% lower serum T4, and about 3-fold elevated serum TSH levels. Notably, the FVB-Ala92-Dio2 thyroid glands showed transcriptional evidence of endoplasmic reticulum stress, unfolded protein response, autophagy, and apoptosis. Female FVB-Ala92-Dio2 mice exhibited a more pronounced thyroid phenotype than males. These findings underscore the critical role of genetic background in modulating the phenotype outcomes of the Thr92Ala-Dio2 polymorphism and highlight its potential implications for understanding variable disease susceptibility in human populations.