A common variant associated with dyslexia reduces expression of the KIAA0319 gene.
A common variant associated with dyslexia reduces expression of the KIAA0319 gene.
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DOI：
10.1371/journal.pgen.1000436
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发表时间：
2009-03
期刊：
影响因子：
4.5
通讯作者：
Monaco AP
中科院分区：
文献类型：
--
作者：
Dennis MY;Paracchini S;Scerri TS;Prokunina-Olsson L;Knight JC;Wade-Martins R;Coggill P;Beck S;Green ED;Monaco AP
大量的遗传关联研究表明，人类染色体6p22上的KIAA0319基因与阅读障碍易感性有关。致病变异体(S)仍不清楚，但可能调节基因表达，因为(1)与阅读障碍相关的单倍型与KIAA0319的表达减少有关，(2)KIAA0319的第一外显子区域与已发现的最强关联。在这里，我们检验了一种假设，即导致KIAA0319表达降低的变异(S)位于基因转录起始点附近的风险单倍型上。我们在KIAA0319上游的风险单倍型上发现了七个单核苷酸多态，并确定其中三个与多个阅读相关性状密切相关。使用包含KIAA0319上游区域的荧光素酶表达载体，我们表征了最小启动子和额外的假定转录调节区。这表明Rs9461045的次要等位基因，在我们的样本中显示出与阅读障碍最强的关联(最大p值 = 0.0001)，在神经元和非神经元细胞系中都表现出荧光素酶的表达减少。此外，我们发现这个与阅读障碍相关的rs9461045等位基因的存在创建了一个核蛋白结合位点，很可能是转录沉默蛋白Oct-1。使用siRNA下调神经细胞系SHSY5Y中Oct-1的表达，可以将KIAA0319的表达从风险单倍型恢复到接近非风险单倍型的表达。因此，我们的研究准确地指出了一种常见的变异，即改变阅读障碍候选基因的功能，并提供了一个分析复杂遗传特征的分子基础所需的战略方法的说明性例子。阅读障碍，或阅读障碍，是一种常见的疾病，由遗传和环境因素引起。遗传学研究表明，许多基因可能在阅读障碍中起作用。我们对一个这样的基因(KIAA0319)进行了功能鉴定，以确定可能影响基因表达并导致疾病的变异(S)。我们发现了一个位于KIAA0319蛋白编码区之外的变异体，它降低了该基因的表达。该变异体为转录因子Oct-1创建了一个结合位点。先前的研究表明，Oct-1与基因上游的特定DNA序列结合可以减少该基因的表达。在这种情况下，KIAA0319表达的减少可能会导致大脑中与阅读能力有关的区域发育不当。这是第一次发现与阅读障碍有关的功能变异。更广泛地说，我们的研究说明了可用于识别导致其他复杂遗传疾病的突变的步骤。
Numerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s) remains unknown but may modulate gene expression, given that (1) a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2) the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s) responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001), confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits. Dyslexia, or reading disability, is a common disorder caused by both genetic and environmental factors. Genetic studies have implicated a number of genes as candidates for playing a role in dyslexia. We functionally characterized one such gene (KIAA0319) to identify variant(s) that might affect gene expression and contribute to the disorder. We discovered a variant residing outside of the protein-coding region of KIAA0319 that reduces expression of the gene. This variant creates a binding site for the transcription factor OCT-1. Previous studies have shown that OCT-1 binding to a specific DNA sequence upstream of a gene can reduce the expression of that gene. In this case, reduced KIAA0319 expression could lead to improper development of regions of the brain involved in reading ability. This is the first study to identify a functional variant implicated in dyslexia. More broadly, our study illustrates the steps that can be utilized for identifying mutations causing other complex genetic disorders.
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