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Molecular genetic research on the peculiar form of Becker Muscular Dystrophy (BMD), where cardiac muscle is preferentially involved

针对贝克尔肌营养不良症（BMD）这一特殊形式的分子遗传学研究，其中心肌优先受累

基本信息

批准号：
06670680
负责人：
TAKEDA Shin-ichi
金额：
$ 1.34万
依托单位：
National Center of Neurology and Psychiatry
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

Cardiac muscle was preferentially involved in some patients of BMD,and we found the deletion of the DMD gene around intron 1 in these patients. We started further study based on the hypothesis that preferential cardiac involvement was due to aberrant transcriptional regulation of the DMD gene.1) Incidence of the BMD families with cardiac involvement in JapanWe investigated the incidence of BMD families with cardiac involvement in Japan in collaboration with Department of Medicine in Shinsyu University. BMD patients with cardiac involvement who have the deletion between exon 45-48 of the DMD gene, showed typical skeletal muscle symptom for BMD.However the group of BMD patients with cardiac involvement, who revealed the deletion around the 5'-end of the DMD gene, often developed cardiac involvement without overt skeletal muscle symptom.2) Analysis of the DMD gene of BMD family with cardiac involevementWe collected the BMD families, which show preferential cardiac involvement and the deletion around 5'-end of the gene. The molecular genetic study using DNA marker for intron 1 of the gene revealed that preferential cardiac involvement cannot be explained by the deletion of the particular part of the intron 1.3) Transcriptional regulation of the DMD gene in cardiac muscleWe prepared the series of constructions which contain various lengths of the DMD gene promoter with CAT reporter gene. We transfected these constructs into the C2 cells or rat neonatal primary cardiac cells. The promoter construct, which has up to-102bp of the gene showed the highest activities in skeletal and cardiac cells. The fragment contained the CArG box sequence and the deletion or the mutation of the CArG box sequence leads the loss of activities in both cells.

一些BMD患者优先涉及心肌，我们在这些患者中发现内含子1周围的DMD基因缺失。我们开始了进一步的研究，基于优先参与心脏是由于异常转录调控的DMD基因的假设。1)日本BMD家族心脏受累的发生率我们与新大学医学系合作调查了日本BMD家族心脏受累的发生率。伴有心脏病变的骨骼肌骨病患者，DMD基因45-48外显子缺失，表现出典型的骨骼肌症状。然而，发现DMD基因5'端缺失的伴有心脏受累的BMD患者组，经常出现心脏受累而没有明显的骨骼肌症状。2)与心脏相关的BMD家族DMD基因分析我们收集了BMD家族，这些家族表现出优先参与心脏和基因5'端缺失。利用该基因内含子1的DNA标记进行分子遗传学研究，发现不能用内含子特定部分的缺失来解释心脏优先参与。1.3)DMD基因在心肌中的转录调控我们制备了一系列包含不同长度的DMD基因启动子和CAT报告基因的结构。我们将这些构建体转染到C2细胞或大鼠新生原代心肌细胞中。该基因的启动子结构在骨骼和心脏细胞中显示出最高的活性，其长度高达102bp。该片段含有CArG box序列，CArG box序列的缺失或突变导致两个细胞的活性丧失。