Pihlajaniemi T, Dickson L A, Pope F M, Korhonen V R, Nicholls A, Prockop D J, Myers J C
J Biol Chem. 1984 Nov 10;259(21):12941-4.
Osteogenesis imperfecta (OI), a brittle-bone disorder, constitutes a major group of the inherited diseases of connective tissue. We have been studying an autosomal recessive form of OI in which the severely affected patient has inherited two abnormal pro-alpha 2(I) collagen alleles from consanguinous parents. Previously, nuclease S1 mapping was employed to localize a defect in the mRNA coding for the pro-alpha 2(I) collagen carboxyl-propeptide. The mutation prevents incorporation of pro-alpha 2(I) chains into the normal type I procollagen heterotrimer resulting in secretion of only pro-alpha 1(I) homotrimers. Here we report complete characterization of the corresponding region of the altered gene. Polyacrylamide gel electrophoresis and Southern blot hybridization showed a small homozygous deletion in the pro-alpha 2(I) collagen gene of the patient and a heterozygous pattern in both parents. Genomic cloning of the patient's DNA revealed a four nucleotide frameshift deletion in exon 1 near the end of translation which apparently instigates use of a new termination codon four nucleotides 3' to the original site. The mutation identified in this OI patient directly demonstrates the critical role of the carboxyl-propeptides in chain selection and assembly during the biosynthesis of procollagen.
成骨不全症（OI）是一种脆骨病，是结缔组织遗传性疾病中的一个主要类型。我们一直在研究一种常染色体隐性遗传形式的OI，在这种类型中，严重患病的患者从近亲父母那里继承了两个异常的前α2（I）胶原蛋白等位基因。以前，采用核酸酶S1图谱法来定位前α2（I）胶原蛋白羧基前肽的mRNA编码中的一个缺陷。该突变阻止前α2（I）链掺入正常的I型前胶原异源三聚体中，导致仅分泌前α1（I）同三聚体。在此，我们报告了该改变基因相应区域的完整特征。聚丙烯酰胺凝胶电泳和Southern印迹杂交显示，该患者的前α2（I）胶原蛋白基因存在一个小的纯合缺失，而其双亲则呈现杂合模式。对患者DNA进行基因组克隆，发现在翻译末端附近的外显子1中有一个四核苷酸移码缺失，这显然促使在原始位点下游四个核苷酸处使用一个新的终止密码子。在这名OI患者中鉴定出的突变直接证明了羧基前肽在原胶原生物合成过程中的链选择和组装中的关键作用。
