Molecular Besis of MeCP2 null-mutation Model Mouse and Gene Therapy

Rett综合征（RTT）是一种神经发育障碍，与甲基cpg结合蛋白2 （MeCP2）突变有关。然而，基因型与表型之间的相关性尚不清楚。我们对219例RTT患者进行了MeCP2分析。145例患者（66.2%）共鉴定出45种不同的突变。错义突变T158M是McCPZ最常见的突变，发生率为19.1%，其次是4个无义突变，分别为R168X（14.8%）、R270X（13.0%）、R255X（9.6%）和R294X（6.1%）。两种错义突变R133C（33.3%）和R306C（23.3%）以及一种无义突变R294X（13.3%）在30例非典型RTT患者中常见，包括保留的言语变异。已知在半合子雄性（-/y）小鼠中缺失MeCP2可导致rtt样神经症状。我们利用腺病毒载体将MeCP2基因导入纹状体，并与感染Ad进行比较。lacZ(控制)。39天和40天龄的MeCP2-/Y小鼠，在4天和7天后进行了几项行为研究。（每组n=7）。运动能力的进行性恶化见Ad。lacz处理小鼠的Ad明显减弱。MeCP2处理的MeCP2-/Y小鼠。然后，我们用成年雌性MeCP2-/+小鼠进行了体内腺病毒MeCP2基因转导到两纹状体前后的行为研究。治疗后，大多数小鼠的运动障碍活动明显改善。治疗效果在几周内达到显著，但在Ad后6周时达到最大水平。mccp2注射。所有具有自残症状的MeCP2 -/+小鼠均通过McCP2基因治疗完全治愈。综上所述，RTT在出生后和发病后通过MeCP2的表达是可逆的，MeCP2在纹状体的运动和情绪控制中起着重要作用。

Rett syndrome (RTT) is a neurodevelopmental disorder, associated with mutations in the methyl-CpG-binding protein 2 (MeCP2). However, it is unknown the correlation between genotype and the phenotype yet.We performed MeCP2 analysis in 219 patients with RTT. A total of 45 different mutations were identified in 145 patients (66.2%). A missense mutation, T158M was the most common mutation of McCPZ, identified in 19.1%, followed by four nonsense mutations, R168X(14.8%), R270X(13.0%), R255X(9.6%), and R294X(6.1%) in classical RTT. Two missense mutation, R133C (33.3%), and R306C (23.3%), and a nonsense mutation, R294X (13.3%), were common in 30 patients with atypical RTT, including the preserved speech variant. Deletion of MeCP2 in hemizygous male (-/y) mice known to leads to RTT-like neurological symptoms. We transducted MeCP2 gene into the striaturn using adenoviral vector and compared to an infection of Ad.lacZ (control). The, MeCP2-/Y mice at 39 or 40 days old, several behavioral studies were performed 4 and 7 days later. (n=7 each group). The progressive deterioration of locomotion activity see in the Ad.LacZ-treated mice and there was significantly attenuated is the Ad.MeCP2-treated MeCP2-/Y mice. Then we performed the behavior studies before and after in vivo adenoviral MeCP2 gene transduction into the both striatum using the adult female MeCP2-/+ mice. The improvement of the impaired locomotors activity was clearly recognized in most of mice after the treatment. The therapeutic effects were met conspicuous within a few weeks, but then increased and reaches at the maximum level at 6 weeks after Ad.McCP 2 injection. All of the MeCP2 -/+ mice that had represented self-injuries were completely cured of these symptoms by McCP2 gene therapy. In conclusion, RTT is reversible by MeCP2 expression after birth and the onset, and MeCP2 plays essential roles in controlling locomotion and emotion in the striatum.