A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing.
A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing.
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DOI：
10.1016/j.atherosclerosis.2007.01.034
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发表时间：
2007-11-01
期刊：
影响因子：
5.3
通讯作者：
Soutar, A K
中科院分区：
文献类型：
--
作者：
Bourbon, M;Sun, X-M;Soutar, A K
家族性高胆固醇血症(FH)通常是由低密度脂蛋白(LDLR)受体基因突变引起的，这种突变损害了低密度脂蛋白从循环中的清除。通过饮食建议和降脂药物治疗可以降低与FH相关的过早冠心病的风险，但重要的是在早期阶段识别受影响的个体。几个依赖于识别基因组DNA中核苷酸替换的FH基因诊断程序已经启动，但这些程序的有效性取决于区分沉默的核苷酸变体和影响低密度脂蛋白受体功能的突变。在这里，我们描述了LDLR外显子9编码区的一个单核苷酸替换，它是一个明显沉默的多态：CGG(Arg406)到AGG(Arg)。对患者细胞的mRNA分析表明，该突变引入了一个新的剪接位点，用于排除自然剪接位点，并导致该mRNA缺失31bp，预计将导致R406之后的4个密码子提前终止。这一发现强调了仅基于基因组DNA序列进行FH基因诊断时需要注意的事项。
Familial hypercholesterolaemia (FH) is usually caused by mutations in the low density lipoprotein (LDL) receptor gene (LDLR) that impair clearance of LDL from the circulation. The increased risk of premature coronary heart disease associated with FH can be reduced by dietary advice and treatment with lipid-lowering drug therapy, but it is important to identify affected individuals at an early stage. Several programmes for genetic diagnosis of FH that rely on identifying nucleotide substitutions in genomic DNA have been initiated, but the validity of these is dependent on distinguishing between a silent nucleotide variant and a mutation that affects LDL-receptor function. Here we describe a single nucleotide substitution in the coding region of exon 9 of LDLR that is an apparently silent polymorphism: CGG (Arg406) to AGG (Arg). Analysis of mRNA from the patient's cells showed that the mutation introduces a new splice site that is used to the exclusion of the natural splice site and causes a deletion of 31 bp from the mRNA, predicted to introduce premature termination four codons after R406. This finding emphasizes the caution needed in genetic diagnosis of FH based on genomic DNA sequence alone.