4月2號是第五屆世界自閉癥日,，4月4日Nature雜志在線發(fā)表三篇作為特色文章的研究論文表明自閉癥與多個基因突變有關(guān),。
三個新發(fā)現(xiàn)的基因突變與自閉癥有關(guān)。這些研究成果揭開了自閉癥的新的遺傳靶標,，為自閉癥的重要的遺傳變化及導(dǎo)致泛自閉障礙(autism spectrum disorders, ASD)的多個生物學(xué)途徑提供了新的理解,。
基因突變是發(fā)生在DNA鏈上的錯誤，使人具有患某種疾病的風(fēng)險,。在這幾項研究中鑒定的發(fā)生突變的基因—CHD8, SNC2A, and KATNAL2—是通過被稱為外顯子測序的最新基因組測序技術(shù)而發(fā)現(xiàn)的,。研究人員稱，隨著對這些基因的進一步定型研究以及對數(shù)千個家庭的基因測序,，他們將能夠為自閉癥開發(fā)新的治療方法及預(yù)防策略,。
“我們現(xiàn)在已經(jīng)對與自閉癥有關(guān)的大量基因有了很好的判斷，并且已經(jīng)發(fā)現(xiàn)了其中的10%,，”西奈山醫(yī)學(xué)院的Joseph Buxbaum博士說,。“如果我們要解開與ASD有關(guān)的重要基因，我們需要對更多的患者記憶他們的小孩進行研究,。這項工作對于促進自閉癥的治療非常關(guān)鍵,。”
在研究中，ASD研究人員猜測,，自身產(chǎn)生的突變是相當一部分自閉癥發(fā)生的原因,。自身產(chǎn)生的突變指的是那些受影響的小孩中首次出現(xiàn)的突變，是由精子或卵子中的突變發(fā)生而來的,。
由Buxbaum博士發(fā)起的自閉癥測序聯(lián)合會是一個由自閉癥遺傳學(xué)研究者組成的國際團隊,，他們通過大規(guī)模下一代測序?qū)ψ蚤]癥的遺傳學(xué)病因進行研究。在這項研究中,，他們對超過500個家庭（包括父母與小孩）進行測序研究,，檢測了基因組上的蛋白質(zhì)富集區(qū)域。
Buxbaum博士說：“當在許多受影響的小孩中發(fā)現(xiàn)相同的突變,，而在非自閉癥小孩中卻沒有時,，我們相信我們發(fā)現(xiàn)了通過共同作用對大部分自閉癥患者形成影響的突變。我們的研究發(fā)現(xiàn),，由這些突變基因所編碼的蛋白質(zhì)之間的發(fā)應(yīng)超過了我們的預(yù)期,，正是了超過我們預(yù)期的重要相關(guān)性。”
同期作為特色文章發(fā)表在Nature上的另外兩篇論文中的其中一篇由耶魯醫(yī)學(xué)院的Matthew State博士領(lǐng)導(dǎo)完成,。他們首次發(fā)現(xiàn)數(shù)個高度斷裂性突變與ASD相關(guān),。研究結(jié)果表明，在某個基因上的多個變異是形成了ASD的風(fēng)險因子,。另外一篇由華盛頓大學(xué)Evan Eichler博士領(lǐng)導(dǎo)完成的研究發(fā)現(xiàn)與ASD相關(guān)的某些特定突變是親緣性的,。他們的研究結(jié)論還支持了此前的研究成果：年齡相對更大的父親其小孩患ASD的風(fēng)險更高,。（生物谷 bioon.com）
doi:10.1038/nature11011
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Patterns and rates of exonic de novo mutations in autism spectrum disorders
Benjamin M. Neale, Yan Kou, Li Liu, Avi Ma’ayan, Kaitlin E. Samocha, Aniko Sabo, Chiao-Feng Lin, Christine Stevens, Li-San Wang, Vladimir Makarov, Paz Polak, Seungtai Yoon, Jared Maguire, Emily L. Crawford,0 Nicholas G. Campbell,0 Evan T. Geller, Otto Valladares, Chad Schafer, Han Liu, Tuo Zhao, Guiqing Cai, Jayon Lihm, Ruth Dannenfelser, Omar Jabado, Zuleyma Peralta
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1, 2. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes3 as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case–control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
文獻二：De novo mutations revealed by whole-exome sequencing are strongly associated with autism
文獻三：Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
