| Co-Investigator(Kenkyū-buntansha) |
YAMASHITA Yushiro Kurume University, Pediatric, Assistant Professor, 医学部, 講師 (90211630)
KOGA Yasutoshi Kurume University, Pediatric, Professor, 医学部, 教授 (00225400)
KOSAI Kenichiro Kurume University, Cognitive and Molacular Reseach Institute for Brain Diseases, Professor, 高次脳疾患研究所, 教授 (90258418)
KONDO Ikuko Ehime University, Hygiene, Professor, 医学部衛生学, 教授 (20110489)
TAKASHIMA Sachio International University of Health and Welfare, 大学院, 教授 (70038743)
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| Research Abstract |
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.
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