THIS IS WHERE DISCOVERIES ARE BORN!

The researchers from the Medical University of Bialystok (Filip Bossowski, Beata Sawicka, Karolina Stożek, Artur Bossowski) in cooperation with prof. Jukka Kero from the Department of Pediatrics and Adolescent Medicine (Turku University Hospital, Turku, Finland) „Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T knock-in model” in JCI Insight. 

The clinical spectrum of thyrotropin receptor-related (TSHR) diseases ranges from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAM) leading to non-autoimmune hyperthyroidism (NAH). Variations at the TSHR locus are also associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the non-thyroid roles of TSHR and the mechanisms underlying the phenotypic variation in diseases mediated by TSHR remain unclear. In the work presented here, we characterized TSHR variants and factors involved in phenotypic variation in different patient cohorts, the FinnGen database and a mouse model. TSHR CAMs were found in all 16 NAH patients, with one CAM at an unexpected site in the extracellular leucine-rich domain (p.S237N) and another in the transmembrane domain (p.I640V) in two families with different hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants as well as various common non-coding TSHR SNPs significantly associated with thyroid phenotypes, but no other significant association between TSHR variants and more than 2,000 endpoints unrelated to thyroid disease. Finally, our TSHR M453T knock-in model revealed that the phenotype was dependent on the signaling properties of the mutation and was mitigated by increased iodine intake. In conclusion, our data show that TSHR-related disease risk can be modified by variants at the TSHR locus both internally and externally. 

Link to the article: https://doi.org/10.1172/jci.insight.167092