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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 mechanisms, as well as to explore the degree to which these mutations are specific to TSHR compared with pituitary glycoprotein hormone receptors.
Methods:
We examined the data on the TSHR website (www.unvi-leipzeig approximately innerre/TSH) supplemented with recent literature. Comparisons were also made with gain-of-function mutations of lutropin/choriogonadotropin (LH/CGR) 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 mutations. Several residues located mainly in a mutation cluster region (619-639) are shared by both. Germline mutations are more likely to be transitions than transversions compared with somatic mutations. The lack of mutations 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 adjoining third intracellular loop were concordant (P>0.90). We suggest that there is specific clustering of mutations in the juxtacytoplasmic end of TM6 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 other TSHR-specific codons cannot be discounted, nor can genetic factors, when accounting for the variation in the prevalence of TSHR-activating mutations worldwide.
Insights
Germline and somatic thyrotropin receptor (TSHR) mutations differ in location and mechanism. TSHR mutations occur outside typical clusters, unlike other glycoprotein hormone receptors, suggesting unique genetic and environmental influences.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- The thyrotropin receptor (TSHR) is crucial for thyroid hormone regulation.
- Gain-of-function mutations in TSHR can lead to conditions like hyperthyroidism.
- Understanding mutation patterns is key to deciphering receptor function and disease mechanisms.
Purpose of the Study:
- To investigate differences between germline and somatic gain-of-function mutations in TSHR.
- To compare mutation locations and mechanisms in TSHR with other glycoprotein hormone receptors.
- To identify TSHR-specific mutational characteristics.
Main Methods:
- Analysis of TSHR mutation data from a dedicated website and literature.
- Comparative analysis with gain-of-function mutations in lutropin/choriogonadotropin (LH/CGR) and follicle-stimulating hormone receptors (FSHR).
- Examination of mutation sites, mechanisms (transitions vs. transversions), and prevalence.
Main Results:
- Exclusive germline mutations found at specific residues (e.g., 183, 505), while somatic mutations characterize others (e.g., 630, 633).
- Shared mutation sites exist, particularly in the mutation cluster region (619-639) involving TM6 and intracellular loops.
- TSHR mutations show significant differences in site specificity compared to LH/CGR, especially outside the TM6 cluster.
Conclusions:
- TSHR exhibits frequent mutations outside established mutation cluster regions.
- Environmental and genetic factors may contribute to the diverse prevalence of TSHR-activating mutations globally.
- Specific interactions within the LH/CGR receptor, involving TM5 and TM6, may explain distinct mutation clustering compared to TSHR.