Deep intronic GPR143 mutation in a Japanese family with ocular albinism.
Deep intronic GPR143 mutation in a Japanese family with ocular albinism.
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DOI：
10.1038/srep11334
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发表时间：
2015-06-10
影响因子：
4.6
通讯作者：
Imoto I
中科院分区：
文献类型：
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作者：
Naruto T;Okamoto N;Masuda K;Endo T;Hatsukawa Y;Kohmoto T;Imoto I
深度内含子突变作为人类疾病的可能原因经常被忽视。使用全外显子组测序，我们分析了一个日本家庭的基因组DNA，其中两个男性兄弟姐妹受到眼白化病和先天性眼球震颤的影响。虽然在候选基因中没有发现编码区的突变或拷贝数改变，但在GPR 143内含子5内的新内含子突变c.659-131 T > G在受影响的同胞中被鉴定为半合子，在未受影响的母亲中被鉴定为杂合子。预测该突变在内含子5内产生一个隐蔽剪接供体位点，并在上游41 nt处激活一个隐蔽受体位点，导致在异常转录物中插入一个具有提前终止密码子的框外41-bp假外显子的编码序列，这通过微基因实验得到证实。这一结果扩大了GPR 143的突变谱，并表明下一代测序与计算机模拟和实验分析相结合的实用性，以改善这种疾病的分子诊断。
Deep intronic mutations are often ignored as possible causes of human disease. Using whole-exome sequencing, we analysed genomic DNAs of a Japanese family with two male siblings affected by ocular albinism and congenital nystagmus. Although mutations or copy number alterations of coding regions were not identified in candidate genes, the novel intronic mutation c.659-131 T > G within GPR143 intron 5 was identified as hemizygous in affected siblings and as heterozygous in the unaffected mother. This mutation was predicted to create a cryptic splice donor site within intron 5 and activate a cryptic acceptor site at 41nt upstream, causing the insertion into the coding sequence of an out-of-frame 41-bp pseudoexon with a premature stop codon in the aberrant transcript, which was confirmed by minigene experiments. This result expands the mutational spectrum of GPR143 and suggests the utility of next-generation sequencing integrated with in silico and experimental analyses for improving the molecular diagnosis of this disease.