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Generation of a Mouse Spontaneous Autoimmune Thyroiditis Model
Published on: March 17, 2023
Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin
Kristiina Makkonen1,2, Meeri Jännäri1,2, Luís Crisóstomo2
1Department of Clinical Sciences, Faculty of Medicine, and.
Abstract:
The clinical spectrum of thyrotropin receptor-mediated (TSHR-mediated) diseases varies from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAMs) leading to nonautoimmune hyperthyroidism (NAH). Variation at the TSHR locus has also been associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the extrathyroidal roles of TSHR and the mechanisms underlying phenotypic variability among TSHR-mediated diseases remain unclear. Here we identified and characterized TSHR variants and factors involved in phenotypic variability in different patient cohorts, the FinnGen database, and a mouse model. TSHR CAMs were found in all 16 patients with NAH, with 1 CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in 2 families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants as well as distinct common noncoding TSHR SNPs significantly associated with thyroid phenotypes, but there was no other significant association between TSHR variants and more than 2,000 nonthyroid disease endpoints. Finally, our TSHR M453T-knockin model revealed that the phenotype was dependent on the mutation's signaling properties and was ameliorated by increased iodine intake. In summary, our data show that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region as well as by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.
Insights
Thyrotropin receptor (TSHR) variants influence thyroid disease risk and presentation. Genetic variations and iodine intake can modify TSHR-mediated disease phenotypes, necessitating personalized treatment approaches.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- Thyrotropin receptor (TSHR)-mediated diseases encompass a range of conditions, from congenital hypothyroidism to nonautoimmune hyperthyroidism (NAH).
- The extrathyroidal functions of TSHR and the reasons for varied disease presentations remain poorly understood.
- TSHR variations have been linked to metabolic and autoimmune thyroid conditions, but comprehensive analysis is lacking.
Purpose of the Study:
- To identify and characterize TSHR variants and factors contributing to phenotypic variability in TSHR-mediated diseases.
- To investigate the role of genetic and environmental factors in TSHR-related disorders.
- To explore the mechanisms behind the diverse clinical manifestations of TSHR diseases.
Main Methods:
- Analysis of TSHR variants in patient cohorts and the FinnGen database.
- Characterization of novel TSHR constitutively active mutations (CAMs) in patients with NAH.
- Generation and study of a TSHR M453T-knockin mouse model.
Main Results:
- TSHR CAMs were identified in all NAH patients, including novel mutations in extracellular and transmembrane domains.
- FinnGen database screening revealed rare functional TSHR variants and common noncoding SNPs associated with thyroid phenotypes.
- No significant associations were found between TSHR variants and over 2,000 nonthyroid disease endpoints.
- The mouse model demonstrated that TSHR phenotype depends on mutation signaling and is influenced by iodine intake.
Conclusions:
- TSHR-mediated disease risk is influenced by coding and noncoding TSHR variants.
- Altered TSHR signaling and dietary iodine intake are critical modifiers of disease phenotype.
- These findings support the development of personalized treatment strategies for TSHR-related disorders.
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