Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute, Los Angeles, CA 90048, USA.
Thyroid. 2013 Mar;23(3):360-70. doi: 10.1089/thy.2012.0338.
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).
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.
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).
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.
通过用表达人促甲状腺激素（TSH）受体的腺病毒免疫小鼠，诱导 Graves 甲状腺功能亢进。使用重组近交系小鼠家族，我们先前发现，诱导的甲状腺刺激抗体和甲状腺功能亢进的遗传易感性与不同染色体上的基因座相关，表明甲状腺对配体刺激的敏感性存在根本的遗传差异。评估甲状腺敏感性的一种方法是用 TSH 挑战遗传多样化的小鼠品系，并测量血清甲状腺素（T4）的基因型/品系特异性增加。
我们研究了 CXB、BXH 和 AXB/BXA 品系家族的雌性小鼠中 T4 刺激的遗传易感性和遗传控制，这些品系家族先前都研究过诱导性 Graves 甲状腺功能亢进。
在注射 TSH 之前，必须通过抑制内源性 TSH 分泌来抑制 T4 水平。在 51 个重组近交系中，有 50 个雌性小鼠通过每天三次腹腔注射 L-三碘甲状腺原氨酸有效地抑制了血清 T4。在源自 T4 刺激差异的亲本品系的 CXB 和 BXH 系中，TSH 诱导的 T4 刺激的遗传相关性比源自具有相似 TSH 诱导反应的亲本的 AXB/BXA 系更强。与诱导性甲状腺功能亢进（数月后发展）相关的遗传基因座与与急性 TSH 诱导的 T4 反应（数小时）相关的基因座不同。
三种近交系小鼠系的甲状腺对 TSH 刺激的敏感性遗传易感性不同。这些观察结果与人类情况相似，即多个遗传基因座对同一特征有贡献，而不同基因座与不同种族的同一特征相关。在小鼠中突出的遗传基因座中，有三个与人类 TSH 控制基因重叠，或位于其上下游。其他研究表明，可以通过跨物种基因映射来识别人类疾病基因。因此，我们的发现表明，人类可能还有新的甲状腺功能基因有待发现。
