Based on a literature search regarding all published TSHR mutations, this review covers several mutations which are clearly associated with a hyperthyroidism-phenotype, but interestingly show a lack of constitutive activity determined by in vitro characterization.
However, the comparison of the LRA values of sporadic TSHR mutations with LRA values of familial TSHR mutations does show a significantly higher median LRA value for sporadic as compared to familial autosomal dominant hyperthyroidism.
Although hereditary nonautoimmune overt hyperthyroidism is very rare, TSHR activating mutations as a cause of subclinical hyperthyroidism may be more common and should be considered in the differential diagnosis, especially if familial.
In addition, patients harboring the same mutation of the TSHr gene may show wide phenotypic variability with respect to the age at onset, and severity of hyperthyroidism and thyroid growth.
The members of the first family affected by hyperthyroidism, i.e. the mother and her two children, showed a germline mutation, a transition of GCC to GTC in the genomic DNA of the TSH receptor, leading to an exchange of alanine by valine at the position 623.
Our results suggest also that additional natural mutations (especially K183M, N, or Q) in position 183 of TSHr are expected to be found in gestational hyperthyroidism.
Thus, the main conclusions to be drawn from this case are 1) a search for mutations in cases of congenital nonautoimmune hyperthyroidism should not remain restricted to exon 10 of the TSHR gene, because germ-line gain of function mutations of the TSH receptor can be located outside of the transmembrane core of the receptor; and 2) this case illustrates the necessity for careful functional characterization of any novel mutation before a causal relationship to hyperthyroidism can be established.
During pregnancy, the placental hormone human choriogonadotropin (hCG) can cause gestational hyperthyroidism through cross-reaction with the TSH receptor.
The amount of blocking and stimulating TSHRAb were measured in 200 patients with untreated hyperthyroid Graves' disease using several cell lines carrying different TSHR chimera.
Cysteine 390 of the rat thyrotropin (TSH) receptor, when mutated to serine, results in a receptor with a reduced ability of TSH to bind and increase cAMP levels but a preserved ability of thyroid stimulating autoantibodies (TSAbs) from hyperthyroid Graves' patients to increase cAMP levels.
Sequencing of all exons of the TSHR gene in one family with hyperthyroidism revealed a mutation in exon 10 (T6321), which was first identified in toxic adenomas and found to constitutively activate the TSHR.
We describe a family with a new TSHR germline mutation that is associated with euthyroidism in 13 family members and hyperthyroidism in 1 family member.
However, all affected patients with a TSH receptor mutation showed persistent hyperthyroidism regardless of subclinical or overt hyperthyroidism throughout the follow-up.
Description was made of a family with non-autoimmune autosomal dominant hyperthyroidism carrying a novel mutation of TSHR leading to the increment in specific constitutive activity.
We report two different mutations in the TSHR gene of affected members of two large pedigrees with non-autoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia), that involve residues in the third (Val509Ala) and seventh (Cys672Tyr) transmembrane segments.
In addition, patients harboring the same mutation of the TSHr gene may show wide phenotypic variability with respect to the age at onset, and severity of hyperthyroidism and thyroid growth.