Functional studies of new TSH receptor (TSHr) mutations identified in patients affected by hypothyroidism or isolated hyperthyrotrophinaemia

Clinical Endocrinology
Giuseppina De MarcoMassimo Tonacchera

Abstract

To establish the role of new TSH receptor (TSHr) variants (P27T, E34 K, R46P, D403N, W488R and M527T) recently identified in children with congenital hypothyroidism (CH) or subclinical hypothyroidism (SH) with a thyroid gland of normal size. TSHr variants were obtained by mutagenesis. Wild-type (wt) and TSHr mutants were expressed in COS cells and cAMP assay, (125)I-TSH binding and microchip flow cytometry analyses were performed. D403N and M527T mutants showed a lower cAMP response to bovine TSH (bTSH) with respect to the wtTSHr. R46P and W488R mutants did not show any response to bTSH stimulation in terms of cAMP production. The E34 K mutant showed a significantly lower cAMP response to stimulation with bTSH, while P27T had a lower cAMP response only to the highest dose of bTSH used. P27T, E34 K, D403N and M527T mutants showed a lower TSH binding capacity with respect to the wtTSHr. R46P and W488R mutants did not show any TSH binding. E34 K, D403N, M527T, R46P and W488R TSHr variants seem to cause a functional abnormality of the receptor which is responsible for the observed phenotype. The P27T TSHr variant does not seem to play a functional role in the pathogenesis of CH and should be considered as a polymorphism.

References

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Citations

Nov 17, 2012·Journal of Clinical Research in Pediatric Endocrinology·Alessandra CassioLilia Baldazzi
Jun 1, 2017·Clinical Endocrinology·Maria Cristina VigoneGiovanna Weber
Oct 28, 2010·Netherlands Heart Journal : Monthly Journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation·E OttenJ P van Tintelen
Dec 7, 2016·Auto- Immunity Highlights·Ricardo Núñez MiguelBernard Rees Smith
Jul 1, 2011·Journal of Pediatric Endocrinology & Metabolism : JPEM·Erik A C AlvesLuiz C Santana-da-silva
Oct 13, 2009·The Journal of Clinical Endocrinology and Metabolism·Annalisa NicolettiAlessandra Cassio
Apr 30, 2016·The Journal of Biological Chemistry·Joerg SchaarschmidtRalf Paschke

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