[Frontiers in Bioscience 15, 913-933, June 1, 2010]

[Frontiers in Bioscience 15, 913-933, June 1, 2010]

Genetic defects, thyroid growth and malfunctions of the TSHR in pediatric patients

Heike Biebermann¹, Franziska Winkler¹, Gunnar Kleinau²

¹Institute of Experimental Pediatric Endocrinology, Charite Universitatsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany, ²Leibniz-Institut fur Molekulare Pharmakologie (FMP), Robert-Rossle-Straße 10, 13125 Berlin, Germany

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Genetic defects of the TSHR: 3.1. Somatic mutations; 3.2. Germline mutations
4. Inactivating TSHR mutations as the molecular cause of hyperthyrotropinemia and congenital . hyperthyroidism: 4.1. Clinical aspects; 4.2. Molecular and structural aspects of receptor inactivation
5. Constitutively activating TSHR mutations as the molecular cause of non-autoimmune hyperthyroidism: 5.1. Clinical aspects; 5.2. Molecular and structural aspects of TSHR activation by mutation
6. Dimerization of the TSHR: 6.1. Hypothetical TSHR dimer-interface
7. TSHR mutations and thyroid growth
8. Concluding remarks
9. Acknowledgment
10. References

1. ABSTRACT

Naturally occurring activating and inactivating mutations of the thyrotropin receptor (TSHR) were found as a molecular cause of diseases in patients suffering from non-autoimmune hyperthyroidism and syndromes of thyrotropin resistance, respectively. These mutations are mostly functionally characterized in vitro and therefore, they represent an excellent tool to study structure-function relationships of this G-protein-coupled receptor. In this review, we summarize published germline mutations of the TSHR with focus on 1) the phenotype of (pediatric) patients, 2) potential genotype/phenotype correlations, 3) structural implications for receptor activation and inactivation, 4) the impact on thyroid growth, and 5) finally on aspects of TSHR dimerization. In conclusion, this comprehensive analysis of medical and biological data opens an avenue to understand genetic defects and malfunctions of the TSHR in molecular detail and in their entirety. This knowledge is important to refine our insights in non-autoimmune diseases caused by defects of the TSHR gene and it might help to develop pharmacological means for compensation of uncontrolled thyroid growth.