Gregory Simon G, Connelly Jessica J, Towers Aaron J, Johnson Jessica, Biscocho Dhani, Markunas Christina A, Lintas Carla, Abramson Ruth K, Wright Harry H, Ellis Peter, Langford Cordelia F, Worley Gordon, Delong G Robert, Murphy Susan K, Cuccaro Michael L, Persico Antonello, Pericak-Vance Margaret A
Duke Center for Human Genetics, DUMC, Durham, NC, USA.
BMC Med. 2009 Oct 22;7:62. doi: 10.1186/1741-7015-7-62.
Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders.
We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR).
Our analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls.
Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder.See the related commentary by Gurrieri and Neri: http://www.biomedcentral.com/1741-7015/7/63.
自闭症是一系列儿童发育过程中的行为和认知障碍，具有高度遗传性。尽管已采用多种方法来鉴定与自闭症发生相关的基因，但不到10%的自闭症病例可归因于单基因疾病。
我们描述了使用高分辨率全基因组平铺路径微阵列和比较基因组杂交技术，来鉴定来自多个自闭症家庭的119名先证者中的拷贝数变异。接下来，我们通过亚硫酸氢盐测序对一名先证者及其家族进行DNA甲基化分析，并将此分析扩展至来自独立数据集的自闭症病例和匹配对照的外周血及颞叶皮质DNA的甲基化分析。我们还通过定量实时聚合酶链反应（PCR）评估了颞叶皮质组织中催产素受体（OXTR）基因的表达。
我们的分析发现，一名自闭症先证者及其患有强迫症症状的母亲存在一个包含催产素受体基因OXTR（MIM登录号：167055）的基因组缺失，该基因之前被认为与自闭症有关。先证者的患病同胞没有这个缺失，但可能通过DNA甲基化导致的异常基因沉默表现出该基因的表观遗传失调。对已知调控OXTR表达的CpG岛进行的进一步DNA甲基化分析，确定了几个CpG二核苷酸，与对照样本相比，在独立的自闭症个体数据集中，这些二核苷酸在外周血细胞和颞叶皮质中的DNA甲基化状态呈现出独立的统计学显著增加。与这些CpG二核苷酸甲基化增加相关的是，我们发现与对照组相比，在年龄和性别匹配的自闭症病例的颞叶皮质组织中，OXTR mRNA表达降低。
这些数据共同为OXTR和催产素信号通路在自闭症病因学中的作用提供了进一步证据，并且首次表明OXTR的表观遗传调控与该疾病的发生有关。见Gurrieri和Neri的相关评论：http://www.biomedcentral.com/1741-7015/7/63 。
