Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk.
Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk.
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DOI：
10.1016/j.cell.2017.03.007
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发表时间：
2017-03-23
期刊：
影响因子：
64.5
通讯作者：
Garcia-Blanco MA
中科院分区：
文献类型：
--
作者：
Galarza-Muñoz G;Briggs FBS;Evsyukova I;Schott-Lerner G;Kennedy EM;Nyanhete T;Wang L;Bergamaschi L;Widen SG;Tomaras GD;Ko DC;Bradrick SS;Barcellos LF;Gregory SG;Garcia-Blanco MA
多发性硬化症（MS）是一种自身免疫性疾病，其中T细胞攻击中枢神经系统（CNS）中的神经元，导致脱髓鞘和神经缺陷。MS风险增加的驱动因素是可溶性形式的白细胞介素-7受体α链基因（sIL 7 R），由IL 7 R外显子6的选择性剪接产生。在这里，我们确定了RNA解旋酶DDX 39 B作为该外显子的有效激活剂，因此是sIL 7 R的阻遏物，并发现DDX 39 B与MS风险有很强的遗传相关性。事实上，我们发现DDX 39 B的5′ UTR中的遗传变异减少了DDX 39 B mRNA的翻译并增加了MS风险。重要的是，该DDX 39 B变体与IL 7 R外显子6中的等位基因变体显示出强的遗传和功能上位性。本研究确定了人类生物上位性的发生，并提供了对IL 7 R外显子6剪接调控及其对MS风险影响的机制见解。多发性硬化症（MS）是一种损害中枢神经系统的自身免疫性疾病，其风险增加与白细胞介素7受体（IL 7 R）mRNA的可变剪接改变相关，导致可溶性IL 7 R升高。在这里，我们确定的RNA解旋酶DDX 39 B作为一个有效的调节IL-7受体剪接，可溶性IL-7受体形成的阻遏物和MS风险的修改器。我们发现MS相关的DDX 39 B 5′ UTR变体降低了DDX 39 B蛋白水平，并显示出与IL 7 R变体的强遗传和功能上位性。
Multiple Sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R), produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5′ UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk. Increased risk for Multiple Sclerosis (MS), an autoimmune disease that damages the central nervous system, is associated with altered alternative splicing of Interleukin 7 receptor (IL7R) mRNAs that leads to elevated soluble IL7R. Here, we identify the RNA helicase DDX39B as a potent regulator of IL7R splicing, a repressor of soluble IL7R formation and a modifier of MS risk. We show that an MS-associated DDX39B 5′ UTR variant reduces DDX39B protein levels and shows strong genetic and functional epistasis with variants in IL7R.