Mechanisms of thyrotropin receptor–mediated phenotype variability deciphered by gene mutations and M453T-knockin model
Kristiina Makkonen, Meeri Jännäri, Luís Crisóstomo, Matilda Kuusi, Konrad Patyra, Vladyslav Melnyk, Veli Linnossuo, Johanna Ojala, Rowmika Ravi, Christoffer Löf, Juho-Antti Mäkelä, Päivi Miettinen, Saila Laakso, Marja Ojaniemi, Jarmo Jääskeläinen, Markku Laakso, Filip Bossowski, Beata Sawicka, Karolina Stożek, Artur Bossowski, Gunnar Kleinau, Patrick Scheerer, FinnGen FinnGen, Mary Pat Reeve, Jukka Kero
Kristiina Makkonen, Meeri Jännäri, Luís Crisóstomo, Matilda Kuusi, Konrad Patyra, Vladyslav Melnyk, Veli Linnossuo, Johanna Ojala, Rowmika Ravi, Christoffer Löf, Juho-Antti Mäkelä, Päivi Miettinen, Saila Laakso, Marja Ojaniemi, Jarmo Jääskeläinen, Markku Laakso, Filip Bossowski, Beata Sawicka, Karolina Stożek, Artur Bossowski, Gunnar Kleinau, Patrick Scheerer, FinnGen FinnGen, Mary Pat Reeve, Jukka Kero
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Research Article Endocrinology Genetics

Mechanisms of thyrotropin receptor–mediated phenotype variability deciphered by gene mutations and M453T-knockin model

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.

Authors

Kristiina Makkonen, Meeri Jännäri, Luís Crisóstomo, Matilda Kuusi, Konrad Patyra, Vladyslav Melnyk, Veli Linnossuo, Johanna Ojala, Rowmika Ravi, Christoffer Löf, Juho-Antti Mäkelä, Päivi Miettinen, Saila Laakso, Marja Ojaniemi, Jarmo Jääskeläinen, Markku Laakso, Filip Bossowski, Beata Sawicka, Karolina Stożek, Artur Bossowski, Gunnar Kleinau, Patrick Scheerer, FinnGen FinnGen, Mary Pat Reeve, Jukka Kero

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Figure 1

Phenotypic, genotypic, and clinical data of 4 modified pedigrees with familial nonautoimmune hyperthyroidism.

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Phenotypic, genotypic, and clinical data of 4 modified pedigrees with fa...
(A) Illustrates pedigrees of 4 kindreds with overt nonautoimmune hyperthyroidism across 3 generations with an extracellular TSHR Ser237Asn (p.S237N) mutation among all affected cases of Family A. Families B and C are nonconsanguineous Finnish kindreds with a TSHR Ile640Val (p.I640V) mutation in all affected cases presenting overt (Family B) and subclinical (Family C) hyperthyroidism (patient #285 is euthyroid carrier). Family D shows individuals with subclinical to overt hyperthyroidism and a TSHR Ala485Val (p.A485V) mutation in 3 affected family members. (B) Representative chromatograms of the identified mutations and their corresponding WT family members. The mutation, zygosity, age at diagnosis, and serum TSH, free thyroxine (fT4) and free triiodothyronine (fT3) hormone levels at the time of diagnosis are listed below the pedigree, except for Family C, for which the ranges of TSH, fT4, and fT3 serum levels during several years of follow-up are shown. ** indicates no DNA available; star indicates radioiodine; and triangle indicates thyroidectomy treatments; # indicates that this person is a carrier of the TSHR Val233Met mutation. Hyperthyroid cases are marked with red color, and mutation carriers are marked with vertical line. In 2 individuals (patients #266 and #279) of Family B, hyperthyroidism was activated during the first trimester of pregnancy. Patients #74, #75, and #295 have subclinical hyperthyroidism and have not required antithyroid treatment during 20 (patient #74), 10 (patient #75), or 2 (patient #295) years of follow-up.