title: The human thyrotropin receptor is highly mutable: a review of gain-of-function mutations.
abstract: OBJECTIVE
  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.
authors.affiliation: Osancor Biotech Inc, Watford, Hertfordshire, UK. farid.obi@cwcom.net
authors.forename: N R
authors.initials: NR
authors.lastname: Farid
authors.forename: V
authors.initials: V
authors.lastname: Kascur
authors.forename: C
authors.initials: C
authors.lastname: Balazs
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D009153:Mutagens; D009154:Mutation; D011962:Receptors, FSH / Q000737:chemistry / Q000235:genetics; D011974:Receptors, LH / Q000737:chemistry / Q000235:genetics; D011989:Receptors, Thyrotropin / Q000737:chemistry / Q000235:genetics*
chemical_list: D009153:Mutagens; D011962:Receptors, FSH; D011974:Receptors, LH; D011989:Receptors, Thyrotropin; D004247:DNA