Genomic and epigenetic evidence for oxytocin receptor deficiency in autism.
Genomic and epigenetic evidence for oxytocin receptor deficiency in autism.
复制标题
DOI：
10.1186/1741-7015-7-62
复制
发表时间：
2009-10-22
期刊：
影响因子：
9.3
通讯作者：
Pericak-Vance MA
中科院分区：
文献类型：
--
作者：
Gregory SG;Connelly JJ;Towers AJ;Johnson J;Biscocho D;Markunas CA;Lintas C;Abramson RK;Wright HH;Ellis P;Langford CF;Worley G;Delong GR;Murphy SK;Cuccaro ML;Persico A;Pericak-Vance MA
自闭症包括儿童发育的一系列行为和认知障碍，并且已知具有高度遗传性。虽然许多方法已被用于确定与自闭症发展有关的基因，但只有不到10%的自闭症病例归因于单基因疾病。我们描述了使用高分辨率全基因组芯片和比较基因组杂交，以确定拷贝数变异119个先证者从多重自闭症家庭。接下来，我们通过亚硫酸氢盐测序在先证者及其家人中进行了DNA甲基化分析，将该分析扩展到自闭症病例和来自独立数据集的匹配对照的外周血和颞叶皮层DNA的甲基化分析。我们还评估了催产素受体（OXTR）基因表达的颞叶皮质组织定量实时聚合酶链反应（PCR）。我们的分析揭示了含有催产素受体基因OXTR的基因组缺失（MIM登录号：167055），以前涉及自闭症，是目前在自闭症先证者和他的母亲谁表现出强迫症的症状。先证者的受影响的兄弟姐妹没有这种缺失，而是可能通过DNA甲基化引起的异常基因沉默表现出该基因的表观遗传失调。已知调节OXTR表达的CpG岛的进一步DNA甲基化分析鉴定了几种CpG二核苷酸，其显示与对照样品相比，自闭症个体的独立数据集中外周血细胞和颞叶皮层中DNA甲基化状态的独立统计学显著增加。与这些CpG二核苷酸甲基化的增加相关的是，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层组织中，OXTR mRNA的表达降低。总之，这些数据为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的证据，并首次暗示了OXTR在疾病发展中的表观遗传调节。参见Gurrieri和Neri的相关评论：
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:
登录
查看更多内容
影响因子：
3.5
作者：
Boyar, FZ;Whitney, MM;Driscoll, DJ
通讯作者：
Driscoll, DJ
影响因子：
3.9
作者：
Gillberg, C
通讯作者：
Gillberg, C
影响因子：
30.8
作者：
Iafrate, AJ;Feuk, L;Lee, C
通讯作者：
Lee, C
影响因子：
11.2
作者：
Filipek, PA;Juranek, J;Gargus, JJ
通讯作者：
Gargus, JJ
影响因子：
12.7
作者：
Belichenko, PV;Hagberg, B;Dahlstrom, A
通讯作者：
Dahlstrom, A