Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center
Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center
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DOI：
10.1038/jhg.2010.49
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发表时间：
2010-06-01
影响因子：
3.5
通讯作者：
Matsuo, Masafumi
中科院分区：
文献类型：
--
作者：
Takeshima, Yasuhiro;Yagi, Mariko;Matsuo, Masafumi
Duchenne肌营养不良症(DMD)分子治疗的最新进展需要准确的基因诊断，因为治疗方法是突变特异性的。神户大学临床遗传学数据库用于DMD和Becker肌营养不良症，是一个以医院为基础的数据库，包含442例病例。在传统的基于基因组DNA的方法基础上，结合互补DNA和染色体分析，成功地完成了所有病例的突变检测，建立了日本营养不良症最大的突变数据库。在442例中，包括一个或多个外显子的缺失和重复分别为270例(61%)和38例(9%)。分别有69例(16%)和24例(5%)的核苷酸改变导致无义突变或剪接位点中断。34例(8%)发现小的缺失/插入突变。值得注意的是，还发现了两个反转录转座子插入事件。在四个案例中，dystrophin的cdna分析成功地发现了新的转录本，其中有一个伪外显子是由内含子深处的单核苷酸变化产生的。两例发现X染色体异常。93%的缺失和66%的重复突变病例支持阅读框架规则。对于分子治疗的应用，诱导外显子跳跃被认为是营养不良症治疗的首要任务。在日本的一家转诊中心，首次建立了以医院为基础的营养不良基因突变数据库，数据库的质量和患者数量都达到了最高水平。《人类遗传学杂志》(2010年)55379-388；DOI：10.1038/jhg.2010.49；2010年5月20日在线发布
Recent developments in molecular therapies for Duchenne muscular dystrophy (DMD) demand accurate genetic diagnosis, because therapies are mutation specific. The KUCG (Kobe University Clinical Genetics) database for DMD and Becker muscular dystrophy is a hospital-based database comprising 442 cases. Using a combination of complementary DNA (cDNA) and chromosome analysis in addition to conventional genomic DNA-based method, mutation detection was successfully accomplished in all cases, and the largest mutation database of Japanese dystrophinopathy was established. Among 442 cases, deletions and duplications encompassing one or more exons were identified in 270 (61%) and 38 (9%) cases, respectively. Nucleotide changes leading to nonsense mutations or disrupting a splice site were identified in 69 (16%) or 24 (5%) cases, respectively. Small deletion/insertion mutations were identified in 34 (8%) cases. Remarkably, two retrotransposon insertion events were also identified. Dystrophin cDNA analysis successfully revealed novel transcripts with a pseudoexon created by a single-nucleotide change deep within an intron in four cases. X-chromosome abnormalities were identified in two cases. The reading frame rule was upheld for 93% of deletion and 66% of duplication mutation cases. For the application of molecular therapies, induction of exon skipping was deemed the first priority for dystrophinopathy treatment. At one Japanese referral center, the hospital-based mutation database of the dystrophin gene was for the first time established with the highest levels of quality and patient's number. Journal of Human Genetics (2010) 55, 379-388; doi:10.1038/jhg.2010.49; published online 20 May 2010