Type I osteogenesis imperfecta: a nonfunctional allele for pro alpha 1 (I) chains of type I procollagen.
Type I osteogenesis imperfecta: a nonfunctional allele for pro alpha 1 (I) chains of type I procollagen.
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I 型成骨不全症：I 型原胶原的 pro alpha 1 (I) 链的非功能性等位基因。
DOI：
10.1073/pnas.79.12.3838
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发表时间：
1982
影响因子：
11.1
通讯作者：
Byers,PH
中科院分区：
文献类型：
--
作者：
Barsh,GS;David,KE;Byers,PH
I型成骨不全(OI)是一种主要的遗传性疾病，其临床特征为儿童期骨折、青光眼、频繁的听力损失，并伴有骨和皮肤中I型胶原含量的降低。来自三个患病个体的培养皮肤成纤维细胞产生一半正常水平的I型前胶原，I型前胶原是一种二硫键结合的三聚体，包含两个前α1(I)链和一个前α2(I)链。在正常细胞中，原α1(I)和原α2(I)以2：1的比例合成，并且只分泌组装的分子。相反，OI细胞含有等摩尔量的前α1(I)和前α2(I)，这表明三聚体的组装和分泌受到前α1(I)合成水平的限制。OI细胞中的“额外的”原α2(I)处于非二硫键构型，不会分泌，但显然有助于增加细胞内的降解水平。因此，在这些患者中，I型前胶原的产生减少是前α1(I)合成减少的结果。这些结果表明，I型前胶原中前α链的化学计量比由链的构象而不是它们合成的比例决定，含有多个前α2(I)链的分子没有组装，并且这种杂多分子的产生可以通过控制其中一个亚基的合成来有效地调节。
Type I osteogenesis imperfecta (OI) is a dominantly inherited disease characterized clinically by bone fractures during childhood, blue sclerae, and frequent hearing loss accompanied by a decreased content of type I collagen in bone and skin. Cultured skin fibroblasts from three individuals affected with the disease produce half-normal levels of type I procollagen, a disulfide-bonded trimer that contains two pro alpha 1(I) chains and one pro alpha 2(I) chain. In normal cells, pro alpha 1(I) and pro alpha 2(I) are synthesized in a 2:1 ratio and only assembled molecules are secreted. In contrast, the OI cells contain equimolar amounts of pro alpha 1(I) and pro alpha 2(I), which suggests that trimer assembly and secretion are limited by the level of pro alpha 1(I) synthesis. The "extra" pro alpha 2(I) in the OI cells is in a nondisulfide-bonded configuration and is not secreted but apparently contributes to an increased level of intracellular degradation. Thus, decreased production of type I procollagen in these patients is the result of decreased synthesis of pro alpha 1(I). These results suggest that the stoichiometry of pro alpha chains in type I procollagen is determined by the conformation of the chains rather than the ratio in which they are synthesized, that molecules containing more than a single pro alpha 2(I) chain are not assembled, and that the production of this heteropolymeric molecule may be effectively regulated by controlling the synthesis of only one of the subunits.