Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1 acceptor-site mutation that results in abnormal pro-α1(V) N-propeptides and Ehlers-Danlos syndrome type I
Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1 acceptor-site mutation that results in abnormal pro-α1(V) N-propeptides and Ehlers-Danlos syndrome type I
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DOI：
10.1086/342099
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发表时间：
2002-09-01
影响因子：
9.8
通讯作者：
Greenspan, DS
中科院分区：
文献类型：
--
作者：
Takahara, K;Schwarze, U;Greenspan, DS
埃勒斯-当洛斯综合征 (EDS) I 型（经典型）是一种显性遗传的、遗传异质性结缔组织疾病。已在多个个体中发现编码 V 型胶原蛋白的 COL5A1 和 COL5A2 基因突变。大多数突变影响蛋白质的三螺旋结构域或一个 COL5A1 等位基因的表达。我们在一名 I 型 EDS 患者的 COL5A1 N 前肽编码区中发现了一种新的剪接受体突变 (IVS4-2A-->G)。这种突变的结果很复杂：在主要产品中，外显子 5 和 6 都被跳过；其他产品包括少量仅跳过外显子 5 的产品，以及更少量使用外显子 5 内的神秘受体位点的产品。所有产品均装在框架中。具有异常N-前肽的Pro-α1（V）链被分泌并掺入细胞外基质中，该突变导致胶原纤维结构发生巨大改变。两个外显子跳跃发生在转录本中，其中内含子 5 相对于内含子 4 和 6 被快速去除，留下一个可以整体跳过的大（270 nt）复合外显子。仅跳过外显子 5 的转录本源自内含子 6 先于内含子 5 被去除的转录本。外显子 5 中隐藏受体位点的使用发生在内含子 4 在内含子 5 和 6 之后被去除的转录本中。这些发现表明，内含子去除的顺序在剪接位点突变的结果中起着重要作用，并提供了一个模型来解释为什么多个产物源自单个突变。 剪接位点。
Ehlers-Danlos syndrome (EDS) type I (the classical variety) is a dominantly inherited, genetically heterogeneous connective-tissue disorder. Mutations in the COL5A1 and COL5A2 genes, which encode type V collagen, have been identified in several individuals. Most mutations affect either the triple-helical domain of the protein or the expression of one COL5A1 allele. We identified a novel splice-acceptor mutation (IVS4-2A-->G) in the N-propeptide-encoding region of COL5A1, in one patient with EDS type I. The outcome of this mutation was complex: In the major product, both exons 5 and 6 were skipped; other products included a small amount in which only exon 5 was skipped and an even smaller amount in which cryptic acceptor sites within exon 5 were used. All products were in frame. Pro-alpha1(V) chains with abnormal N-propeptides were secreted and were incorporated into extracellular matrix, and the mutation resulted in dramatic alterations in collagen fibril structure. The two-exon skip occurred in transcripts in which intron 5 was removed rapidly relative to introns 4 and 6, leaving a large (270 nt) composite exon that can be skipped in its entirety. The transcripts in which only exon 5 was skipped were derived from those in which intron 6 was removed prior to intron 5. The use of cryptic acceptor sites in exon 5 occurred in transcripts in which intron 4 was removed subsequent to introns 5 and 6. These findings suggest that the order of intron removal plays an important role in the outcome of splice-site mutations and provide a model that explains why multiple products derive from a mutation at a single splice site.