Congenital hypothyroid goiter with deficient thyroglobulin - Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones
Congenital hypothyroid goiter with deficient thyroglobulin - Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones
复制标题
DOI：
10.1172/jci119112
复制
发表时间：
1996-12-15
影响因子：
15.9
通讯作者：
Arvan, P
中科院分区：
文献类型：
--
作者：
MedeirosNeto, G;Kim, PS;Arvan, P
在对cog/cog小鼠先天性甲状腺功能减退甲状腺肿的分子发病机制的理解方面取得的最新进展，提出了关于某些先天性甲状腺肿的人类亲属中甲状腺球蛋白（甲状腺原激素）成熟的重要问题。我们现在检查了来自两个不相关家族的受影响的兄弟姐妹，他们合成了一种明显正常糖基化的bbb300 kD免疫反应性甲状腺球蛋白。从4例患者的甲状腺组织中，光镜检查显示存在细胞内甲状腺球蛋白，尽管其在甲状腺滤泡腔中不存在，而电子显微镜显示内质网（ER）异常扩张。我们已经从生物化学上证实，大多数甲状腺内甲状腺球蛋白不能到达发生复杂碳水化合物修饰的（高尔基体）腔室。此外，受影响患者的疾病与特异性ER分子伴侣的大量诱导有关，包括hsp90同源物GRP94和hsp70同源物Bip。这些数据表明，这些患者合成了一种突变的甲状腺球蛋白，其折叠/组装缺陷，导致从内质网输出蛋白质的能力显著降低。因此，这些种类患有甲状腺ER储存疾病，这是一种细胞生物学缺陷，在表型上与cog/cog小鼠中发现的无法区分。
Recent advances in understanding the molecular pathogenesis of congenital hypothyroid goiter in cog/cog mice, have raised important questions concerning the maturation of thyroglobulin (the thyroid prohormone) in certain human kindreds with congenital goiter, We have now examined affected siblings from two unrelated families that synthesize an apparently normally glycosylated, >300 kD immunoreactive thyroglobulin, yet have a reduced quantity of intraglandular thyroglobulin and that secreted into the circulation From thyroid tissues of the four patients, light microscopic approaches demonstrated presence of intracellular thyroglobulin despite its absence in thyroid follicle lumina, while electron microscopy indicated abnormal distention of the endoplasmic reticulum (ER). We have confirmed biochemically that most intrathyroidal thyroglobulin fails to reach the (Golgi) compartment where complex carbohydrate modification takes place, Moreover, the disease in the affected patients is associated with massive induction of specific ER molecular chaperones including the hsp90 homolog, GRP94, and the hsp70 homolog, Bip. The data suggest that these patients synthesize a mutant thyroglobulin which is defective for folding/assembly, leading to a markedly reduced ability to export the protein from the ER. Thus, these kindreds suffer from a thyroid ER storage disease, a cell biological defect phenotypically indistinguishable from that found in cog/cog mice.