Takabayashi Shuji, Umeki Kazumi, Yamamoto Etsuko, Suzuki Tohru, Okayama Akihiko, Katoh Hideki
Institute for Experimental Animals, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan.
Mol Endocrinol. 2006 Oct;20(10):2584-90. doi: 10.1210/me.2006-0099. Epub 2006 Jun 8.
Recently, we found a novel dwarf mutation in an ICR closed colony. This mutation was governed by a single autosomal recessive gene. In novel dwarf mice, plasma levels of the thyroid hormones, T3 and T4, were reduced; however, TSH was elevated. Their thyroid glands showed a diffuse goiter exhibiting colloid deficiency and abnormal follicle epithelium. The dwarfism was improved by adding thyroid hormone in the diet. Gene mapping revealed that the dwarf mutation was closely linked to the thyroid peroxidase (Tpo) gene on chromosome 12. Sequencing of the Tpo gene of the dwarf mice demonstrated a C to T substitution at position 1508 causing an amino acid change from arginine (Arg) to cysteine (Cys) at codon 479 (Arg479Cys). Western blotting revealed that TPO protein of the dwarf mice was detected in a microsomal fraction of thyroid tissue, but peroxidase activity was not detected. These findings suggested that the dwarf mutation caused a primary congenital hypothyroidism by TPO deficiency, resulting in a defect of thyroid hormone synthesis.
最近，我们在一个ICR封闭群体中发现了一种新的侏儒突变。这种突变由单个常染色体隐性基因控制。在新型侏儒小鼠中，甲状腺激素T3和T4的血浆水平降低；然而，促甲状腺激素（TSH）升高。它们的甲状腺呈现弥漫性甲状腺肿，表现为胶体缺乏和滤泡上皮异常。通过在饮食中添加甲状腺激素，侏儒症得到改善。基因定位显示，侏儒突变与12号染色体上的甲状腺过氧化物酶（Tpo）基因紧密连锁。对侏儒小鼠Tpo基因的测序表明，在第1508位发生了C到T的替换，导致第479密码子处的氨基酸从精氨酸（Arg）变为半胱氨酸（Cys）（Arg479Cys）。蛋白质免疫印迹法显示，在甲状腺组织的微粒体部分检测到了侏儒小鼠的TPO蛋白，但未检测到过氧化物酶活性。这些发现表明，侏儒突变通过TPO缺乏导致原发性先天性甲状腺功能减退，从而导致甲状腺激素合成缺陷。
