MOLECULAR HETEROGENEITY IN OSTEOGENESIS IMPERFECTA TYPE-I
MOLECULAR HETEROGENEITY IN OSTEOGENESIS IMPERFECTA TYPE-I
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DOI：
10.1002/ajmg.1320450214
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发表时间：
1993-01-15
期刊：
影响因子：
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通讯作者：
BYERS, PH
中科院分区：
文献类型：
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作者：
WILLING, MC;PRUCHNO, CJ;BYERS, PH
成骨不全(OI)I型以骨脆性无明显畸形、骨量减少、正常身高、蓝巩膜和常染色体显性遗传为特征。大多数患者的皮肤成纤维细胞产生的I型胶原大约是预期量的一半，这表明OI I型表型是由各种突变导致的，这些突变改变了COL1A1或COL1A2的表观表达，这两个基因编码I型胶原链。对19个家系受累个体的真皮成纤维细胞用[H-3]Pro进行短脉冲标记后发现，大多数细胞的原-α1(I)：原-α2(I)的合成比例发生了变化，大多数细胞的原-α1(I)的合成减少。狭缝杂交结果显示，这些个体的COL1A1/COL1A2 mRNA的比例与对照组相比，属于不同的组，但大多数降低了COL1A1的mRNA水平。这些数据表明，我们的大多数OI I家族都存在COL1A1突变。对患者基因组DNA进行限制性内切酶分析，COL1A1基因的拷贝数和大小在被检查的家系中都是正常的。我们已经确定了一个3代家系，其中所有受影响的成员都有一个正常的COL1A1等位基因，另一个在基因3‘端附近有5个碱基对缺失。该缺失在翻译阅读框中产生了移位，并预测了拉长的proalpha1(I)链的合成。在第二个家庭中，父亲和儿子有一个外显子缺失，这是由剪接突变造成的。对包括启动子在内的COL1A1基因不同区域的扩增产物的化学切割分析表明，几个个体在COL1A1基因的编码区存在点突变，而一个个体可能在α1(I)羧基末端前肽区域存在小的缺失。我们的数据为OI I型表型中显著的分子异质性提供了证据，并表明各种突变可以导致I型胶原合成减少。
Osteogenesis imperfecta (OI) type I is characterized by bone fragility without significant deformity, osteopenia, normal stature, blue sclerae, and autosomal dominant inheritance. Dermal fibroblasts from most affected individuals produce about half the expected amount of type I collagen, suggesting that the OI type I phenotype results from a variety of mutations which alter the apparent expression of either COL1A1 or COL1A2, the genes encoding the chains of type I collagen. Short-pulse labeling of dermal fibroblasts with [H-3]proline from affected individuals in 19 families indicates that most have alterations in the expected 2:1 synthetic ratio of proalpha1(I): proalpha2(I), with most having decreased production of proalpha1(I). Ratios of COL1A1:COL1A2 mRNA from these individuals, using slot-blot hybridization, indicate that they fall into different groups, but that most have decreased COL1A1 mRNA levels, compared with controls. These data suggest that most of our OI I families have COL1A1 mutations. Copy number and size of the COL1A1 gene by restriction endonuclease analysis of genomic DNA from affected individuals are normal in the families examined. We have identified one 3 generation family in which all affected members have one normal COL1A1 allele and another with a 5 base-pair deletion near the 3' end of the gene. The deletion creates a shift in the translational reading-frame and predicts the synthesis of an elongated proalpha1(I) chain. In a second family, a father and a son have a single exon deletion that results from a splicing mutation. Chemical cleavage analysis of amplified cDNA from affected individuals in different regions of the COL1A1 gene, including the promoter, suggests that several individuals have point mutations within the coding region of the gene, while one individual may have a small deletion within the alpha1(I) carboxyl-terminal propeptide region. Our data provide evidence for significant molecular heterogeneity within the OI type I phenotype and indicate that a variety of mutations can result in decreased synthesis of type I collagen.