Reduced MeCP2 Expression is Frequent in Autism Frontal Cortex and Correlates with Aberrant MECP2 Promoter Methylation
Reduced MeCP2 Expression is Frequent in Autism Frontal Cortex and Correlates with Aberrant MECP2 Promoter Methylation
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DOI：
10.4161/epi.1.4.3514
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发表时间：
2006-10-01
期刊：
影响因子：
3.7
通讯作者：
LaSalle, Janine M.
中科院分区：
文献类型：
--
作者：
Nagarajan, Raman P.;Hogart, Amber R.;LaSalle, Janine M.
编码甲基CpG结合蛋白2（MeCP 2）的MECP 2突变导致了大多数Rett综合征（RTT），这是一种X连锁神经发育障碍。RTT和自闭症都是“广泛性发育障碍”，在明显正常的围产期发育后，都丧失了社交、认知和语言技能，并获得了重复的刻板行为。虽然MECP 2编码突变是自闭症的罕见原因，但以前在自闭症大脑中发现了MeCP 2表达缺陷。为了进一步研究MeCP 2在自闭症谱系障碍（ASD）中的作用，我们确定了自闭症和其他ASD大脑样本中MeCP 2表达缺陷的频率。我们还测试了MECP 2启动子突变或异常启动子甲基化与特发性自闭症病例中表达减少相关的假设。MeCP 2免疫荧光在自闭症和其他神经发育障碍进行了定量的激光扫描细胞术，并与对照死后大脑皮层样品的大型组织芯片。与年龄匹配的对照相比，在11/14个自闭症（79%）、9/9个RTT（100%）、4/4个Angelman综合征（100%）、3/4个Prader-Willi综合征（75%）、3/5个唐氏综合征（60%）和2/2个注意缺陷多动障碍（100%）额叶皮质样品中发现MeCP 2表达显著降低。一名自闭症女性是一种罕见的MECP 2启动子变异杂合子，与MeCP 2表达减少相关。与对照组相比，自闭症男性额叶皮层中MECP 2启动子甲基化的发生率更高。此外，MECP 2启动子甲基化百分比与MeCP 2蛋白表达降低显著相关。这些结果表明，遗传和表观遗传缺陷导致MeCP 2表达减少，可能在自闭症的复杂病因学中很重要。
Mutations in MECP2, encoding methyl CpG binding protein 2 (MeCP2), cause most cases of Rett syndrome (RTT), an X-linked neurodevelopmental disorder. Both RTT and autism are "pervasive developmental disorders" and share a loss of social, cognitive and language skills and a gain in repetitive stereotyped behavior, following apparently normal perinatal development. Although MECP2 coding mutations are a rare cause of autism, MeCP2 expression defects were previously found in autism brain. To further study the role of MeCP2 in autism spectrum disorders (ASDs), we determined the frequency of MeCP2 expression defects in brain samples from autism and other ASDs. We also tested the hypotheses that MECP2 promoter mutations or aberrant promoter methylation correlate with reduced expression in cases of idiopathic autism. MeCP2 immunofluorescence in autism and other neurodevelopmental disorders was quantified by laser scanning cytometry and compared with control postmortem cerebral cortex samples on a large tissue microarray. A significant reduction in MeCP2 expression compared to age-matched controls was found in 11/14 autism (79%), 9/9 RTT (100%), 4/4 Angelman syndrome (100%), 3/4 Prader-Willi syndrome (75%), 3/5 Down syndrome (60%), and 2/2 attention deficit hyperactivity disorder (100%) frontal cortex samples. One autism female was heterozygous for a rare MECP2 promoter variant that correlated with reduced MeCP2 expression. A more frequent occurrence was significantly increased MECP2 promoter methylation in autism male frontal cortex compared to controls. Furthermore, percent promoter methylation of MECP2 significantly correlated with reduced MeCP2 protein expression. These results suggest that both genetic and epigenetic defects lead to reduced MeCP2 expression and may be important in the complex etiology of autism.