Chinese Journal of Contemporary Neurology and Neurosurgery ›› 2015, Vol. 15 ›› Issue (6): 442-447. doi: 10.3969/j.issn.1672-6731.2015.06.005

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Clinical study of DMD gene point mutation causing Becker muscular dystrophy

CAO Ji-qing1, YANG Juan1, LI Ya-qin1, FENG Shan-wei1, CHEN Fei2, ZHENG Hui3, LIANG Ying-yin1, ZHAO Bao-jian4, ZHANG Xu4, ZHANG Hui-li1, ZHU Yu-ling1, ZHANG Cheng1   

  1. 1Department of Neurology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
    2Department of Gynecology and Obstetrics, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, Guangdong, China
    3Department of Neurology, Nanfang Hospital of Southern Medical University, Guangzhou 510515, Guangdong, China
    4Molecular Pathology Center, Hospital Attached to Aeromedicine Institute of Chinese PLA, Beijing 100089, China
  • Online:2015-06-25 Published:2015-07-05
  • Contact: ZHANG Cheng (Email: zhangch6@mail.sysu.edu.cn)
  • Supported by:

    This study was supported by Joint Fund of National Natural Science Foundation of China and Natural Science Foundation of Guangdong Province of China (No. U1032004), National Natural Science Foundation of China (No. 81471280, 81271401), Supporting Program for Science and Technology Research of China (No. 2012BAI09B04) and Science and Technology Plan Project of Guangdong Province (No. 2011A030400006).

DMD 基因点突变致Becker型肌营养不良症临床研究

操基清, 杨娟, 李亚勤, 冯善伟, 陈菲, 郑卉, 梁颖茵, 赵保健, 张旭, 张惠丽, 朱瑜龄, 张成   

  1. 510080 广州,中山大学附属第一医院神经科[操基清(现在湖北省武汉市中心医院神经内科,邮政编码:430014),杨娟(现在南方医科大学珠江医院神经内科,邮政编码:510282),李亚勤,冯善伟,梁颖茵,张惠丽,朱瑜龄,张成];510150 广州医科大学第三附属医院妇产科(陈菲);510515 广州,南方医科大学南方医院神经内科(郑卉);100089 北京,空军航空医学研究所附属医院分子病理中心(赵保健,张旭)
  • 通讯作者: 张成(Email:zhangch6@mail.sysu.edu.cn)
  • 基金资助:

    国家自然科学基金-广东省联合基金重点资助项目(项目编号:U1032004);国家自然科学基金资助项目(项目编号:81471280);国家自然科学基金资助项目(项目编号:81271401);国家科技支撑计划项目(项目编号:2012BAI09B04);广东省科技计划项目(项目编号:2011A030400006)

Abstract:

Background  DMD gene point mutation, mainly nonsense mutation, always cause the most severe Duchenne muscular dystrophy (DMD). However, we also observed some cases of Becker muscular dystrophy (BMD) carrying DMD point mutation. This paper aims to explore the mechanism of DMD point mutation causing BMD, in order to enhance the understanding of mutation types of BMD.  Methods  Sequence analysis was performed in 11 cases of BMD confirmed by typical clinical manifestations and muscle biopsy. The exon of DMD gene was detected non-deletion or duplication by multiplex ligation-dependent probe amplification (MLPA).  Results  Eleven patients carried 10 mutation types without mutational hotspot. Six patients carried nonsense mutations [c.5002G>T, p.(Glu1668X); c.1615C > T, p.(Arg539X); c.7105G > T, p.(Glu2369X); c.5287C > T, p.(Arg1763X); c.9284T > G, p.(Leu3095X)]. One patient carried missense mutation [c.5234G > A, p.(Arg1745His)]. Two patients carried frameshift mutations (c.10231dupT, c.10491delC). Two patients carried splicing site mutations (c.4518 + 3A > T, c.649 + 2T > C).  Conclusions  DMD gene point mutation may result in BMD with mild clinical symptoms. When clinical manifestations suggest the possibility of BMD and MLPA reveals non?deletion or duplication mutation of DMD gene, BMD should be considered. Study on the mechanism of DMD point mutation causing BMD is very important for gene therapy of DMD.

Key words: Muscular dystrophy, Duchenne, Dystrophin, Point mutation

摘要:

研究背景 DMD 基因点突变,主要是无义突变,可以引起基因编码提前终止,使产生的目的蛋白不稳定而降解,导致临床症状较重的Duchenne 型肌营养不良症,而在实际工作中可见临床表型为症状较轻的Becker 型肌营养不良症的DMD 点突变患者。本研究旨在探讨DMD  基因点突变导致Becker 型肌营养不良症的发病机制,以加深对Becker 型肌营养不良症基因突变类型的认识。方法 共11 例临床和肌肉活检明确诊断、多重连接依赖性探针扩增(MLPA)显示DMD  基因外显子非缺失或重复突变的Becker 型肌营养不良症患者,高通量第2 代DNA 测序法检测DMD  基因外显子突变类型。结果 11 例Becker 型肌营养不良症患者携带10 种突变类型,无突变热点;6 例携带无义突变[c.5002G>T,p.(Glu1668X);c.1615C>T,p(. Arg539X);c.7105G>T,p(. Glu2369X);c.5287C>T,p(. Arg1763X);c.9284T>G,p.(Leu3095X)];1 例携带错义突变[c.5234G>A,p.(Arg1745His)];2 例携带框移突变(c.10231dupT,c.10491delC);2 例携带剪切位点突变(c.4518+3A > T,c.649 + 2T > C)。结论 DMD 基因点突变可以引起临床症状较轻的Becker 型肌营养不良症,当MLPA 技术显示DMD  基因为非缺失和重复突变时,切勿漏诊Becker型肌营养不良症,研究其发生机制对基因治疗Duchenne型肌营养不良症有重要借鉴意义。

关键词: 肌营养不良, 杜氏, 肌营养不良蛋白, 点突变