The human thyrotropin receptor is highly mutable: a review of gain-of-function mutations

Objectives: To find whether germline and somatic gain-of-function mutations of the thyrotropin receptor (TSHR) differ in location and/or mutational me chanisms, as well as to explore the degree to which these mutations are spe cific to TSHR compared with pituitary glycoprotein hormone receptors. Methods: We examined the data on the TSHR website (www.unvi-leipzeig simila r to innerre/TSH) supplemented with recent literature. Comparisons were als o made with gain-of-function mutations of lutropin/choriogonadotropin (LH/C GR) and follicle-stimulating hormone receptors (FSHR). Results: Some mutations (at residues 183, 505, 509 and 597) are exclusively germline, whereas mutations at 630 and 633 are characteristic of somatic m utations. Several residues located mainly in a mutation cluster region (619 -639) are shared by both. Germline mutations are more likely to be transiti ons than transversions compared with somatic mutations. The lack of mutatio ns involving deamination of CpG dinucleotides, a common mechanism for C-->T transitions, reflects the low CG prevalence in the mutable regions of TSHR . Comparison of the mutation sites with the equivalent positions in LH/CGR showed a significant difference (P < 0.0001), whereas those in the mutation cluster region comprising the sixth transmembrane helix (TM6) and the adjo ining third intracellular loop were concordant (P > 0.90). We suggest that there is specific clustering of mutations in the juxtacytoplasmic end of TM 6 in LH/CGR, a hydrophobic patch that is tightly packed with a face on TM5 whose sequences diverge from those of TSHR. Conclusions: TSHR exhibited frequent mutations outside the mutation cluster region. A role for a mutagenic environment created by the thyroid for othe r TSHR-specific codons cannot be discounted, nor can genetic factors, when accounting for the variation in the prevalence of TSHR-activating mutations worldwide.