Hyperthyroidism and Papillary Thyroid Carcinoma in Thyrotropin Receptor D633H Mutant Mice
Related Experiment Video
Updated: Feb 6, 2026
Transoral Robotic Total Thyroidectomy and Bilateral Central Regional Lymph Node Dissection for Papillary Thyroid Carcinoma
Published on: September 15, 2023
Holger Jaeschke1, Henriette Undeutsch1, Konrad Patyra1
11 Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku , Turku, Finland .
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.
Insights
Constitutively active thyrotropin receptor (TSHR) mutations cause non-autoimmune hyperthyroidism (NAH). This study developed an in vivo model showing these mutations can lead to thyroid tumors, revealing dynamic disease development.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Constitutively active thyrotropin receptor (TSHR) mutations are a primary cause of non-autoimmune hyperthyroidism (NAH).
- Previous research on TSHR mutations has been limited to in vitro studies, lacking in vivo models to explore disease progression.
Purpose of the Study:
- To establish and characterize an in vivo model for non-autoimmune hyperthyroidism (NAH) using a patient-derived TSHR mutation.
- To investigate the pathophysiology and long-term consequences of a constitutively active TSHR in a murine model.
Main Methods:
- Introduced the patient-derived TSHR D633H mutation into the murine Tshr gene via homologous recombination.
- Analyzed the development of hyperthyroidism and thyroid neoplasms in homozygous and heterozygous mutant mice.
- Assessed thyroid hormone levels, histological changes, and expression of proliferation markers.
Main Results:
- The TSHR D633H mutation induced age-, sex-, and genotype-dependent subclinical and overt hyperthyroidism.
- Homozygous mice developed colloid goiter and flattened thyrocytes by six months.
- Nearly all homozygous mice developed papillary thyroid carcinomas by one year, associated with increased proliferation markers but no common oncogene mutations.
Conclusions:
- This study presents the first in vivo model demonstrating the dynamic, age-, sex-, and genotype-dependent development of NAH.
- A constitutively active TSHR mutation can induce malignant transformation of thyrocytes, leading to papillary thyroid carcinoma.
Related Concept Videos
01:11Papillary Dermis
The dermis might be considered the "core" of the integumentary system, as distinct from the epidermis and hypodermis. It contains blood and lymph vessels, nerves, and other structures, such as hair follicles and sweat glands. The dermis is made of two layers of connective tissue that comprise an interconnected mesh of elastin and collagenous fibers, produced by fibroblasts.
Papillary Layer
The papillary layer is made of loose, areolar connective tissue, which means the collagen...
01:23The Thyroid Gland
The follicles have a central cavity lined by simple cuboidal to squamous epithelial cells called follicular cells. These cells produce the glycoprotein...
01:18Functions of Thyroid Hormones
TH is indispensable for the normal development and maturation of the skeletal, muscular, and nervous systems during fetal and childhood growth. It facilitates bone mineral turnover and regulates protein synthesis in developing tissues, contributing significantly to overall growth and...
01:31Internal Receptors
01:20Synthesis and Regulation of Thyroid Hormones
Upon reaching the thyroid gland, TSH stimulates the follicular cells' active uptake of iodide ions from the blood. The ions diffuse to the apical surface of the cells and are oxidized to iodine. The...
01:39Receptor-mediated Endocytosis