science20121221-4

来自美国华盛顿大学医学院的研究人员使用改进的分子倒置探针技术,对大规模的人类自闭症候选基因进行重测序,结果发现这六个基因——CHD8DYRK1AGRIN2BTBR1PTENTBL1XR1的复发性断裂性突变可能是1%的散发性ASDs的发病原因。

-2012年12月21日《科学》


中文翻译


【题目】利用多重靶定测序法在自闭症谱系障碍患者中鉴定复发性的突变基因

【译文】自闭症谱系障碍(ASDs)的外显子组测序研究已经鉴定出许多新生突变,但很少鉴定到复发性地断裂基因。因此,本研究使用一种改进的分子倒置探针技术,使得超大样本中的候选基因能以超低成本进行重测序。为了演示这种技术的功效,本研究从2446例ASD渊源者中捕获了44个候选基因,并对其进行测序。本研究在16个基因中鉴定到27个新生突变,其中59%的突变表型预测为截短的蛋白质或断裂的剪接。本研究估计六个基因——CHD8DYRK1AGRIN2BTBR1PTENTBL1XR1的复发性断裂性突变可能是1%的散发性ASDs的发病原因。本研究结果支持特异性基因与相反的亚型之间的关系,如CHD8-畸形巨头和DYRK1A-头小畸形,及重复验证β-连环蛋白–染色质重塑网络对ASD发病的重要性。

英文原稿


[Title]: Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

[Authors]: Brian J. O’Roak, Laura Vives, Wenqing Fu, Jarrett D. Egertson, Ian B. Stanaway, Ian G. Phelps, Gemma Carvill, Akash Kumar, Choli Lee, Katy Ankenman, Jeff Munson, Joseph B. Hiatt, Emily H. Turner, Roie Levy, Diana R. O’Day, Niklas Krumm, Bradley P. Coe, Beth K. Martin, Elhanan Borenstein, Deborah A. Nickerson, Heather C. Mefford, Dan Doherty, Joshua M. Akey, Raphael Bernier, Evan E. Eichler, and Jay Shendure

[Abstract]: Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes—CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1—may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin–chromatin-remodeling network to ASD etiology.

原文地址

http://www.sciencemag.org/content/338/6114/1619.abstract

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