Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome
Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome
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DOI：
10.1007/s00439-002-0830-3
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发表时间：
2002-12-01
期刊：
影响因子：
5.3
通讯作者：
Green, PM
中科院分区：
文献类型：
--
作者：
King, K;Flinter, FA;Green, PM
X 连锁形式的 Alport 综合征是由 Xq22 中的 COL4A5 基因突变引起的。这种大型多外显子基因过去很难筛选，多项研究仅检测到约 50% 的突变。我们报告了三种新的内含子突变，它们可能在一定程度上解释了这种低成功率，并证明内含子深处的单碱基变化可以而且确实会导致疾病：一种突变在内含子内创建一个新的供体剪接位点，从而导致包含一个新的框内神秘外显子；第二个突变产生新的外显子剪接增强子序列（ESE），该序列促进包含终止密码子的神秘外显子的剪接；第三位患者由于受体剪接位点之前的聚嘧啶束内的碱基取代而表现出外显子跳跃。如果使用逐个外显子 DNA 筛查方法，这三个病例都会被漏掉。
The X-linked form of Alport syndrome is caused by mutations in the COL4A5 gene in Xq22. This large multiexonic gene has, in the past, been difficult to screen, with several studies detecting only about 50% of mutations. We report three novel intronic mutations that may, in part, explain this poor success rate and demonstrate that single base changes deep within introns can, and do, cause disease: one mutation creates a new donor splice site within an intron resulting in the inclusion of a novel in-frame cryptic exon; a second mutation results in a new exon splice enhancer sequence (ESE) that promotes splicing of a cryptic exon containing a stop codon; a third patient exhibits exon skipping as a result of a base substitution within the polypyrimidine tract that precedes the acceptor splice site. All three cases would have been missed using an exon-by-exon DNA screening approach.