King Kathy, Flinter Frances A, Nihalani Vandana, Green Peter M
Division of Medical and Molecular Genetics, 7th Floor Guy's Tower, GKT school of Medicine, King's College, SE1 9RT London, UK.
Hum Genet. 2002 Dec;111(6):548-54. doi: 10.1007/s00439-002-0830-3. Epub 2002 Sep 14.
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.
X连锁型奥尔波特综合征由位于Xq22的COL4A5基因突变引起。这个多外显子的大基因过去很难进行筛查，多项研究仅检测到约50%的突变。我们报告了三个新的内含子突变，这可能部分解释了这种低成功率，并证明内含子深处的单个碱基变化能够且确实会导致疾病：一个突变在一个内含子内产生了一个新的供体剪接位点，导致包含一个新的框内隐蔽外显子被包含在内；第二个突变产生了一个新的外显子剪接增强子序列（ESE），促进了一个含有终止密码子的隐蔽外显子的剪接；第三个患者由于位于受体剪接位点之前的多嘧啶序列内的一个碱基替换而出现外显子跳跃。使用逐个外显子的DNA筛查方法，这三例都可能会被漏检。
