Premature chain termination is a unifying mechanism for COL1A1 null alleles in osteogenesis imperfecta type I cell strains.
Premature chain termination is a unifying mechanism for COL1A1 null alleles in osteogenesis imperfecta type I cell strains.
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发表时间：
1996-10
影响因子：
9.8
通讯作者：
M. Willing;S. Deschenes;Rebecca L. Slayton;Erik J. Roberts
中科院分区：
文献类型：
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作者：
M. Willing;S. Deschenes;Rebecca L. Slayton;Erik J. Roberts
无义突变和移码突变预测翻译的提前终止，通常会导致突变等位基因的转录物数量急剧减少（无义介导的 mRNA 衰减）。在某些基因中，这些突变还会影响 RNA 剪接并诱导包含无义密码子的外显子的跳跃。为了开始剖析提前终止如何改变 COL1A1 基因的 RNA 代谢，我们研究了分布在该基因外显子 11-49 上的无义突变和移码突变。这些突变最初是在 10 个不相关的 1 型成骨不全症 (OI) 家族中发现的。我们观察到，在受影响个体的细胞总细胞和核 RNA 提取物中，突变等位基因的 mRNA 稳态量显着减少，表明无义介导的 COL1A1 RNA 衰变是一种核现象。基因内突变的位置不影响这一观察结果。没有一个突变会引起包含突变的外显子的跳跃，或者对于移码，具有新终止位点的下游外显子的跳跃。我们的数据表明，大部分 COL1A1 基因中的无义突变和移码突变导致无效等位基因，这与可预测的轻度临床表型（OI 1 型）相关。
Nonsense and frameshift mutations, which predict premature termination of translation, often cause a dramatic reduction in the amount of transcript from the mutant allele (nonsense-mediated mRNA decay). In some genes, these mutations also influence RNA splicing and induce skipping of the exon that contains the nonsense codon. To begin to dissect how premature termination alters the metabolism of RNA from the COL1A1 gene, we studied nonsense and frameshift mutations distributed over exons 11-49 of the gene. These mutations were originally identified in 10 unrelated families with osteogenesis imperfecta (OI) type 1. We observed marked reduction in steady-state amounts of mRNA from the mutant allele in both total cellular and nuclear RNA extracts of cells from affected individuals, suggesting that nonsense-mediated decay of COL1A1 RNA is a nuclear phenomenon. Position of the mutation within the gene did not influence this observation. None of the mutations induced skipping of either the exon containing the mutation or, for the frameshifts, the downstream exons with the new termination sites. Our data suggest that nonsense and frameshift mutations throughout most of the COL1A1 gene result in a null allele, which is associated with the predictable mild clinical phenotype, OI type 1.