High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.
High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.
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DOI：
10.1371/journal.pone.0035003
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Margulies D
中科院分区：
文献类型：
--
作者：
Kelleher RJ 3rd;Geigenmüller U;Hovhannisyan H;Trautman E;Pinard R;Rathmell B;Carpenter R;Margulies D
识别自闭症遗传变异影响的共同分子通路对于理解疾病发病机制和设计有效的治疗方法非常重要。在这里，我们测试的假设，罕见的遗传变异的代谢型谷氨酸受体（mGluR）信号通路有助于自闭症的易感性。在两个独立的下一代平台上，通过对来自290例非综合征型自闭症病例和300例种族匹配对照的合并样本进行高通量多重测序，鉴定了编码mGluR信号通路组分的基因中的单核苷酸变体。该分析揭示了自闭症病例中mGluR通路中罕见功能变体的显著富集。在自闭症病例中发现了以前与综合征型自闭症谱系障碍有关的三种途径基因TSC 1，TSC 2和SHANK 3的罕见，潜在有害变体的更高负担，这表明这些基因的遗传变异也有助于非综合征型自闭症的风险。此外，我们的分析确定HOMER 1，它编码一个突触后密度定位的支架蛋白，与Shank 3相互作用，以调节mGluR活性，作为一种新的自闭症风险基因。罕见的，潜在有害的HOMER 1变异独特地在自闭症人群中鉴定，影响功能重要的蛋白质区域或调控序列，并与受影响家庭的儿童中的自闭症密切共分离。我们还鉴定了罕见的ASD相关编码变异，预测其对Ras/MAPK级联反应的组分具有破坏性影响。总的来说，这些研究结果表明，改变下游的mGluRs信号有助于非综合征型自闭症的发病机制。
Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism.