Kuivaniemi H, Tromp G, Prockop D J
Department of Biochemistry and Molecular Biology, Jefferson Institute of Molecular Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
FASEB J. 1991 Apr;5(7):2052-60. doi: 10.1096/fasebj.5.7.2010058.
More than 70 mutations in the two structural genes for type I procollagen (COL1A1 and COL1A2) have been found in probands with osteogenesis imperfecta, a heritable disease of children characterized by fragility of bone and other tissues rich in type I collagen. The mutations include deletions, insertions, RNA splicing mutations, and single-base substitutions that convert a codon for glycine to a codon for an amino acid with a bulkier side chain. With a few exceptions, the most severe phenotypes of the disease are explained largely by synthesis of structurally defective pro alpha chains of type I procollagen that either interfere with the folding of the triple helix or with self-assembly of collagen into fibrils. The results emphasize the extent to which the zipperlike folding of the collagen triple helix and the self-assembly of collagen fibrils depend on the principle of nucleated growth whereby a few subunits form a nucleus and the nucleus is then propagated to generate a large structure with a precisely defined architecture. The principle of nucleated growth is a highly efficient mechanism for the assembly of large structures, but biological systems that depend extensively on nucleated growth are highly vulnerable to mutations that cause synthesis of structurally abnormal but partially functional subunits. Recently, several mutations in three other collagen genes (COL2A1, COL3A1, and COL4A5) have been found in probands with genetic diseases involving tissues rich in these collagens. Most of the probands have rare genetic diseases but a few appear to have phenotypes that are difficult to distinguish from more common disorders such as osteoarthritis, osteoporosis, and aortic aneurysms. Therefore, the results suggest that mutations in procollagen genes may cause a wide spectrum of both rare and common human diseases.
在患有成骨不全症的先证者中，已发现I型前胶原的两个结构基因（COL1A1和COL1A2）有70多种突变。成骨不全症是一种儿童遗传性疾病，其特征是骨骼和其他富含I型胶原的组织脆弱。这些突变包括缺失、插入、RNA剪接突变以及单碱基替换，后者将甘氨酸密码子转换为具有较大侧链的氨基酸密码子。除少数例外，该疾病最严重的表型很大程度上是由I型前胶原结构缺陷的前α链合成所导致的，这些前α链要么干扰三螺旋的折叠，要么干扰胶原自组装成原纤维。这些结果强调了胶原三螺旋的拉链样折叠和胶原原纤维的自组装在多大程度上依赖于成核生长原理，即少数亚基形成一个核，然后该核扩展以生成具有精确确定结构的大结构。成核生长原理是组装大结构的一种高效机制，但广泛依赖成核生长的生物系统极易受到导致合成结构异常但部分功能正常的亚基的突变的影响。最近，在患有涉及富含这些胶原的组织的遗传疾病的先证者中，发现了另外三个胶原基因（COL2A1、COL3A1和COL4A5）的几种突变。大多数先证者患有罕见的遗传疾病，但少数人的表型似乎难以与骨关节炎、骨质疏松症和主动脉瘤等更常见的疾病区分开来。因此，这些结果表明前胶原基因的突变可能导致广泛的罕见和常见人类疾病。
