Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T knock-in model.

The clinical spectrum of thyrotropin receptor (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 one CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in two families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants, as well as distinct common non-coding TSHR SNPs significantly associated with thyroid phenotypes, but no other significant association between TSHR variants and over 2,000 non-thyroid disease endpoints. Finally, our TSHR M453T knock-in model revealed that the phenotype was dependent on the mutation´s signaling properties and was ameliorated by increased iodine intake. In summary, our data shows that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region, and by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.