Morrow Eric M, Yoo Seung-Yun, Flavell Steven W, Kim Tae-Kyung, Lin Yingxi, Hill Robert Sean, Mukaddes Nahit M, Balkhy Soher, Gascon Generoso, Hashmi Asif, Al-Saad Samira, Ware Janice, Joseph Robert M, Greenblatt Rachel, Gleason Danielle, Ertelt Julia A, Apse Kira A, Bodell Adria, Partlow Jennifer N, Barry Brenda, Yao Hui, Markianos Kyriacos, Ferland Russell J, Greenberg Michael E, Walsh Christopher A
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Science. 2008 Jul 11;321(5886):218-23. doi: 10.1126/science.1157657.
To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.
为了寻找自闭症谱系障碍的遗传病因，我们研究了父母有共同祖先的家庭，以增强遗传因素的作用。我们绘制了几个基因座，其中一些包含可能是突变的大型遗传性纯合缺失。最大的缺失涉及多个基因，包括原钙黏蛋白10（PCDH10）和自闭症1缺失基因（DIA1，即c3orf58），其表达水平会随着神经元活动而变化，神经元活动是参与学习基础突触变化的基因的一个标志。包括钠氢交换体9（NHE9）在内的一部分基因，在父母无血缘关系的患者中显示出其他潜在突变。我们的研究结果突出了“纯合性定位”在自闭症等异质性疾病中的效用，但也表明神经活动后基因表达的缺陷调控可能是看似多样的自闭症突变所共有的一种机制。
