A1 Refereed original research article in a scientific journal
Hyperthyroidism and Papillary Thyroid Carcinoma in Thyrotropin Receptor D633H Mutant Mice
Authors: Holger Jaeschke, Henriette Undeutsch, Konrad Patyra, Christoffer Löf, Markus Eszlinger, Moosa Khalil, Meeri Jännäri, Kristiina Makkonen, Jorma Toppari, Fu-Ping Zhang, Matti Poutanen, Ralf Paschke, Jukka Kero
Publisher: MARY ANN LIEBERT, INC
Publication year: 2018
Journal: Thyroid
Journal name in source: THYROID
Journal acronym: THYROID
Volume: 28
Issue: 10
First page : 1372
Last page: 1386
Number of pages: 15
ISSN: 1050-7256
DOI: https://doi.org/10.1089/thy.2018.0041
Abstract
Background: Constitutively active thyrotropin receptor (TSHR) mutations are the most common etiology of non-autoimmune hyperthyroidism (NAH). Thus far, the functionality of these mutations has been tested in vitro, but the in vivo models are lacking.Methods: To understand the pathophysiology of NAH, the patient-derived constitutively active TSHR D633H mutation was introduced into the murine Tshr by homologous recombination.Results: In this model, both subclinical and overt hyperthyroidism was observed, depending on the age, sex, and genotype. Homozygous mice presented hyperthyroidism at two months of age, while heterozygous animals showed only suppressed thyrotropin. Interestingly, at six months of age, thyroid hormone concentrations in all mutant mice were analogous to wild-type mice, and they showed colloid goiter with flattened thyrocytes. Strikingly, at one year of age, nearly all homozygous mice presented large papillary thyroid carcinomas. Mechanistically, this papillary thyroid carcinoma phenotype was associated with an overactive thyroid and strongly increased stainings of proliferation-, pERK-, and NKX2-1 markers, but no mutations in the hot-spot areas of common oncogenes (Braf, Nras, and Kras) were found.Conclusions: This is the first study to reveal the dynamic age-, sex-, and genotype-dependent development of NAH. Furthermore, the study shows that a constitutively active TSHR can trigger a malignant transformation of thyrocytes.
Background: Constitutively active thyrotropin receptor (TSHR) mutations are the most common etiology of non-autoimmune hyperthyroidism (NAH). Thus far, the functionality of these mutations has been tested in vitro, but the in vivo models are lacking.Methods: To understand the pathophysiology of NAH, the patient-derived constitutively active TSHR D633H mutation was introduced into the murine Tshr by homologous recombination.Results: In this model, both subclinical and overt hyperthyroidism was observed, depending on the age, sex, and genotype. Homozygous mice presented hyperthyroidism at two months of age, while heterozygous animals showed only suppressed thyrotropin. Interestingly, at six months of age, thyroid hormone concentrations in all mutant mice were analogous to wild-type mice, and they showed colloid goiter with flattened thyrocytes. Strikingly, at one year of age, nearly all homozygous mice presented large papillary thyroid carcinomas. Mechanistically, this papillary thyroid carcinoma phenotype was associated with an overactive thyroid and strongly increased stainings of proliferation-, pERK-, and NKX2-1 markers, but no mutations in the hot-spot areas of common oncogenes (Braf, Nras, and Kras) were found.Conclusions: This is the first study to reveal the dynamic age-, sex-, and genotype-dependent development of NAH. Furthermore, the study shows that a constitutively active TSHR can trigger a malignant transformation of thyrocytes.
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