Epigenetic overlap in autism-spectrum neurodevelopmental disorders:: MECP2 deficiency causes reduced expression of UBE3A and GABRB3
Epigenetic overlap in autism-spectrum neurodevelopmental disorders:: MECP2 deficiency causes reduced expression of UBE3A and GABRB3
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DOI：
10.1093/hmg/ddi045
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发表时间：
2005-02-15
影响因子：
3.5
通讯作者：
LaSalle, JM
中科院分区：
文献类型：
--
作者：
Samaco, RC;Hogart, A;LaSalle, JM
自闭症是一种常见的神经发育障碍，其遗传病因复杂。 Rett 综合征（一种由 MECP2 突变引起的 X 连锁显性障碍）和 Angelman 综合征（一种由母体 15q11-q13 或 UBE3A 缺陷引起的印记障碍）与自闭症有表型和遗传重叠。 MECP2 编码甲基 CpG 结合蛋白 2，该蛋白充当甲基化基因构建体的转录阻遏蛋白，但令人惊讶的是，它不是维持印记基因表达所必需的。在这里，我们检验了以下假设：MECP2 缺陷可能会影响 UBE3A 和邻近自闭症候选基因 GABRB3 的表达水平，但不一定影响印记表达。使用多种定量方法，包括免疫荧光自动定量和组织微阵列上激光扫描细胞术的原位杂交、免疫印迹和 TaqMan PCR。结果表明，与对照组相比，两种不同的 Mecp2 缺陷小鼠品系以及人类 Rett、Angelman 和自闭症大脑中 UBE3A/E6AP 表达存在显着缺陷。尽管在 Mecp2 缺失脑中几个印记转录本的等位基因表达没有观察到差异，但 Ube3a 有义表达显着降低，与蛋白质的减少一致。通过定量免疫印迹，来自 15q11-q13 的非印记基因 GABRB3（编码 GABAA 受体的 03 亚基）在多个 Rett、Angelman 和自闭症脑样本以及 Mecp2 缺陷小鼠的脑样本中也显示出表达显着降低。这些结果表明，在 Rett、Angelman 和自闭症中，15q11-q13 内的基因失调存在重叠途径，并暗示 MeCP2 参与了产后哺乳动物大脑中 UBE3A 和 GABRB3 表达的调节。
Autism is a common neurodevelopmental disorder of complex genetic etiology. Rett syndrome, an X-linked dominant disorder caused by MECP2 mutations, and Angelman syndrome, an imprinted disorder caused by maternal 15q11-q13 or UBE3A deficiency, have phenotypic and genetic overlap with autism. MECP2 encodes methyl-CpG-binding protein 2 that acts as a transcriptional repressor for methylated gene constructs but is surprisingly not required for maintaining imprinted gene expression. Here, we test the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 without necessarily affecting imprinted expression. Multiple quantitative methods were used including automated quantitation of immunofluorescence and in situ hybridization by laser scanning cytometry on tissue microarrays, immunoblot and TaqMan PCR. The results demonstrated significant defects in UBE3A/ E6AP expression in two different Mecp2 deficient mouse strains and human Rett, Angelman and autism brains compared with controls. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. A non-imprinted gene from 15q11-q13, GABRB3, encoding the 03 subunit of the GABAA receptor, also showed significantly reduced expression in multiple Rett, Angelman and autism brain samples, and Mecp2 deficient mice by quantitative immunoblot. These results suggest an overlapping pathway of gene dysregulation within 15q11-q13 in Rett, Angelman and autism and implicate MeCP2 in the regulation of UBE3A and GABRB3 expressions in the postnatal mammalian brain.