Background: Graves' hyperthyroidism is induced by immunizing mice with adenovirus expressing the human thyrotropin (TSH)-receptor. Using families of recombinant-inbred mice, we previously discovered that genetic susceptibility to induced thyroid-stimulating antibodies and hyperthyroidism are linked to loci on different chromosomes, indicating a fundamental genetic difference in thyroid sensitivity to ligand stimulation. An approach to assess thyroid sensitivity involves challenging genetically diverse lines of mice with TSH and measuring the genotype/strain-specific increase in serum thyroxine (T4).
Methods: We investigated genetic susceptibility and genetic control of T4 stimulation by 10 mU bovine TSH in female mice of the CXB, BXH, and AXB/BXA strain families, all previously studied for induced Graves' hyperthyroidism.
Results: Before TSH injection, T4 levels must be suppressed by inhibiting endogenous TSH secretion. Three daily intraperitoneal L-triiodothyronine injections efficiently suppressed serum T4 in females of 50 of 51 recombinant inbred strains. T4 stimulation by TSH was more strongly linked in CXB and BXH sets, derived from parental strains with divergent T4 stimulation, than in AXB/BXA strains generated from parents with similar TSH-induced responses. Genetic loci linked to the acute TSH-induced T4 response (hours) were not the same as those linked to induced hyperthyroidism (which develops over months).
Conclusions: Genetic susceptibility for thyroid sensitivity to TSH stimulation was distinct for three families of inbred mouse lines. These observations parallel the human situation with multiple genetic loci contributing to the same trait and different loci associated with the same trait in different ethnic groups. Of the genetic loci highlighted in mice, three overlap with, or are located up or downstream, of human TSH-controlling genes. Other studies show that human disease genes can be identified through cross-species gene mapping of evolutionary conserved processes. Consequently, our findings suggest that novel thyroid function genes may yet be revealed in humans.