Kim P S, Hossain S A, Park Y N, Lee I, Yoo S E, Arvan P
Division of Endocrinology and Metabolism, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA.
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9909-13. doi: 10.1073/pnas.95.17.9909.
Newly synthesized thyroglobulin (Tg), the major secretory glycoprotein of the thyroid gland, folds and homodimerizes in the endoplasmic reticulum (ER) before its export to the site of iodination, where it serves as the precursor for thyroid hormone synthesis. In families with defective Tg export, affected individuals suffer from a thyroidal ER storage disease characterized by a distended thyrocyte ER containing misfolded Tg, along with induced ER molecular chaperones. Inherited as an autosomal recessive trait, deficient Tg causes congenital hypothyroidism in newborns that, if untreated, results in goiter along with serious cognitive and growth defects. Recently, a similar phenotype has been observed in inbred cog/cog mice, although the precise molecular defect has remained undefined. Here, we have isolated and cloned a full-length 8.5-kb Tg cDNA from cog/cog mice and unaffected isogenic AKR/J mice. Comparison of the complete sequences reveals that cog/cog mice express a Leu-2263 --> Pro missense mutation in the acetylcholinesterase-homology domain of Tg. Heterologous expression studies in COS cells indicate that cog Tg exhibits a severe defect in exit from the ER. Site-directed mutagenesis of cog Tg to convert the single amino acid back to Leu-2263 restores normal Tg secretion. We conclude that the cog mutation in Tg is responsible for this ER storage disease that causes thyroid dyshormonogenesis.
新合成的甲状腺球蛋白（Tg）是甲状腺的主要分泌性糖蛋白，在被转运至碘化部位之前，先在内质网（ER）中折叠并形成同型二聚体，在碘化部位它作为甲状腺激素合成的前体。在Tg转运缺陷的家族中，受累个体患有甲状腺内质网储存疾病，其特征为甲状腺细胞内质网扩张，含有错误折叠的Tg以及诱导产生的内质网分子伴侣。Tg缺陷作为常染色体隐性性状遗传，可导致新生儿先天性甲状腺功能减退，若不治疗，会导致甲状腺肿大以及严重的认知和生长缺陷。最近，在近交系cog/cog小鼠中也观察到了类似的表型，尽管其确切的分子缺陷尚不清楚。在此，我们从cog/cog小鼠和未受影响的同基因AKR/J小鼠中分离并克隆了全长8.5 kb的Tg cDNA。完整序列比较显示，cog/cog小鼠在Tg的乙酰胆碱酯酶同源结构域中表达Leu-2263→Pro错义突变。在COS细胞中的异源表达研究表明，cog Tg在内质网输出方面存在严重缺陷。将cog Tg的单个氨基酸位点定向突变为Leu-2263可恢复正常的Tg分泌。我们得出结论，Tg中的cog突变是导致这种引起甲状腺激素合成障碍的内质网储存疾病的原因。
