Identification of a point mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse.
Identification of a point mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse.
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DOI：
10.1210/mend.8.2.8170469
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发表时间：
1994-02
影响因子：
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通讯作者：
S. Stein;E. L. Oates;C. R. Hall;R. M. Grumbles;L. M. Fernandez;N. A. Taylor;D. Puett;S. Jin
中科院分区：
文献类型：
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作者：
S. Stein;E. L. Oates;C. R. Hall;R. M. Grumbles;L. M. Fernandez;N. A. Taylor;D. Puett;S. Jin
hyt/hyt甲状腺功能减退小鼠具有常染色体隐性遗传、胎仔发病、与TSH低反应性相关的重度甲状腺功能减退症，并与TSH升高相关。我们以前的工作表明，甲状腺功能减退症和TSH低反应性可能是由于甲状腺hyt/hytTSH受体（TSHr）突变所致。基于野生型BALB/cBY +/+小鼠TSHr基因整个编码区的DNA测序，与大鼠TSHr基因相比，+/+ TSHr在核苷酸和氨基酸残基水平上分别具有92%和94%的同一性。与+/+ TSHr的编码区相比，hyt/hyt TSHr的编码区在核苷酸位置1666处具有单个碱基变化，CCG至CTG，这导致跨膜结构域IV中氨基酸位置556处高度保守的脯氨酸被亮氨酸取代。该突变通过定点诱变引入野生型人TSHr中，并在COS-7细胞中瞬时表达。虽然大小和丰度的突变体TSHr mRNA的mRNA的性质没有影响，TSH结合和TSH在转染细胞中的反应被废除。有必要进一步研究，以澄清Pro到Leu的替代如何干扰细胞表面的受体表达或影响TSH结合。突变的这些功能后果似乎解释了在hyt/hyt小鼠中观察到的TSH低反应性和甲状腺功能减退。
The hyt/hyt hypothyroid mouse has an autosomal recessive, fetal-onset, severe hypothyroidism related to TSH hyporesponsiveness and associated with elevated TSH. Our previous work has suggested that the hypothyroidism and TSH hyporesponsiveness may result from a mutation in the hyt/hyt TSH receptor (TSHr) of the thyroid gland. Based on DNA sequencing of the entire coding region of the TSHr gene from the wild-type BALB/cBY +/+ mouse, the +/+ TSHr is 92% and 94% identical at the nucleotide and amino acid residue levels, respectively, compared to the rat TSHr gene. The coding region of the hyt/hyt TSHr, compared to that of the +/+ TSHr, has a single base change, CCG to CTG, at nucleotide position 1666, which leads to the replacement of a highly conserved proline at amino acid position 556 with a leucine in transmembrane domain IV. This mutation was introduced by site-directed mutagenesis into the wild-type human TSHr and transiently expressed in COS-7 cells. Although the size and abundance of the mutant TSHr mRNA suggested that there was no effect on the nature of the mRNA, TSH binding and the response to TSH in transfected cells were abolished. Further studies are necessary to clarify how the Pro to Leu replacement interferes with receptor expression on the cell surface or influences TSH binding. These functional consequences of the mutation appear to account for the observed TSH hyporesponsiveness and hypothyroidism in the hyt/hyt mouse.