Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping
Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping
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DOI：
10.1007/s00439-005-0070-4
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发表时间：
2006-02-01
期刊：
影响因子：
5.3
通讯作者：
Andresen, BS
中科院分区：
文献类型：
--
作者：
Madsen, PP;Kibæk, M;Andresen, BS
短/支链酰基辅酶A脱氢酶缺乏症（SBCADD）是一种常染色体隐性遗传的L-异亮氨酸代谢障碍。关于这种酶缺陷相关的临床表现知之甚少，因为它只在有限数量的患者中报道。由于血液中C5-肉毒碱的存在可能表明SBCADD，这种疾病可以通过基于MS/MS的常规新生儿筛查来检测。因此，重要的是要获得更多的知识的临床表现和突变谱SBCADD。在本研究中，我们研究了两个不相关的家庭SBCADD，无论是与癫痫发作和ps（y）chorionic延迟为主要临床特征。一个家庭说明了一个事实，即受影响的个人也可能没有症状。此外，一名患者新生儿血斑C5-酰基肉毒碱的正常水平强调了一个事实，即新生儿筛查MS/MS目前缺乏检测SBCADD的灵敏度。到目前为止，已经报道了SBCAD基因中的七种突变，但只有三种经过了实验测试。在这里，我们确定并表征SBCAD基因中的IVS 3 +3A > G突变（c.303+3A > G），并提供证据表明该突变在两个家族中都是致病的。使用微基因方法，我们表明IVS 3 +3A > G突变导致外显子3跳跃，尽管它似乎没有破坏5'剪接位点的共有序列。基于这些结果和大量的文献实例，我们认为这种类型的突变（IVS+3A > G）仅在非共有（弱）5'剪接位点的情况下诱导错误剪接。序列的统计分析显示，其中+3A > G突变引起外显子跳跃和疾病的5'剪接位点的野生型形式平均比随机的5'剪接位点组弱。这一发现与解释其他疾病基因中这种类型突变的功能后果有关。
Short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) is an autosomal recessive disorder of L-isoleucine catabolism. Little is known about the clinical presentation associated with this enzyme defect, as it has been reported in only a limited number of patients. Because the presence of C5-carnitine in blood may indicate SBCADD, the disorder may be detected by MS/MS-based routine newborn screening. It is, therefore, important to gain more knowledge about the clinical presentation and the mutational spectrum of SBCADD. In the present study, we have studied two unrelated families with SBCADD, both with seizures and ps(y)chomotor delay as the main clinical features. One family illustrates the fact that affected individuals may also remain asymptomatic. In addition, the normal level of newborn blood spot C5-acylcarnitine in one patient underscores the fact that newborn screening by MS/MS currently lacks sensitivity in detecting SBCADD. Until now, seven mutations in the SBCAD gene have been reported, but only three have been tested experimentally. Here, we identify and characterize an IVS3+3A > G mutation (c.303+3A > G) in the SBCAD gene, and provide evidence that this mutation is disease-causing in both families. Using a minigene approach, we show that the IVS3+3A > G mutation causes exon 3 skipping, despite the fact that it does not appear to disrupt the consensus sequence of the 5' splice site. Based on these results and numerous literature examples, we suggest that this type of mutation (IVS+3A > G) induces missplicing only when in the context of non-consensus (weak) 5' splice sites. Statistical analysis of the sequences shows that the wild-type versions of 5' splice sites in which +3A > G mutations cause exon skipping and disease are weaker on average than a random set of 5' splice sites. This finding is relevant to the interpretation of the functional consequences of this type of mutation in other disease genes.