Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1
Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1
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DOI：
10.1038/nature04422
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发表时间：
2006-02-23
期刊：
影响因子：
64.8
通讯作者：
Tupler, R
中科院分区：
文献类型：
--
作者：
Gabellini, D;D'Antona, G;Tupler, R
面肩肱型肌营养不良症（FSHD）是一种常染色体显性神经肌肉疾病，不是由于蛋白质编码基因内的经典突变（1，2）。相反，几乎所有FSHD患者都携带位于染色体4 q35上的整数个串联3.3-腺苷酸酶重复单元（称为D4 Z4）的缺失（参考文献3）。D4 Z4含有转录沉默子，其缺失导致位于D4 Z4上游的4 q35基因在FSHD骨骼肌中的不适当过表达（参考文献4）。为了鉴定FSHD发病机制的基因，我们产生了在骨骼肌中选择性过表达4 q35基因FRG 1、FRG 2或ANT 1的转基因小鼠。我们发现FRG 1转基因小鼠发展为具有人类疾病特征的肌营养不良症;相比之下，FRG 2和ANT 1转基因小鼠似乎正常。FRG 1是一种核蛋白，几条证据表明它参与前信使RNA剪接（5-7）。我们发现，在FRG 1转基因小鼠和FSHD患者的肌肉中，特定的前mRNA发生异常的选择性剪接。总的来说，我们的研究结果表明，FSHD的结果不适当的过度表达FRG 1在骨骼肌，这导致异常的选择性剪接的特定前mRNA。
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is not due to a classical mutation within a protein-coding gene(1,2). Instead, almost all FSHD patients carry deletions of an integral number of tandem 3.3-kilobase repeat units, termed D4Z4, located on chromosome 4q35 (ref. 3). D4Z4 contains a transcriptional silencer whose deletion leads to inappropriate overexpression in FSHD skeletal muscle of 4q35 genes located upstream of D4Z4 ( ref. 4). To identify the gene responsible for FSHD pathogenesis, we generated transgenic mice selectively overexpressing in skeletal muscle the 4q35 genes FRG1, FRG2 or ANT1. We find that FRG1 transgenic mice develop a muscular dystrophy with features characteristic of the human disease; by contrast, FRG2 and ANT1 transgenic mice seem normal. FRG1 is a nuclear protein and several lines of evidence suggest it is involved in pre-messenger RNA splicing(5-7). We find that in muscle of FRG1 transgenic mice and FSHD patients, specific pre-mRNAs undergo aberrant alternative splicing. Collectively, our results suggest that FSHD results from inappropriate overexpression of FRG1 in skeletal muscle, which leads to abnormal alternative splicing of specific pre-mRNAs.