Differential expression of dystrophin isoforms in strains of mdx mice with different mutations
Differential expression of dystrophin isoforms in strains of mdx mice with different mutations
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DOI：
10.1093/hmg/5.8.1149
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发表时间：
1996-08-01
影响因子：
3.5
通讯作者：
Chamberlain, JS
中科院分区：
文献类型：
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作者：
Im, WB;Phelps, SF;Chamberlain, JS
dystrophin基因的突变是Duchenne和Becker肌营养不良症（DMD/BMD）的原因，dystrophin的表达和功能的研究得益于mdx小鼠（DMD/BMD的动物模型）的使用。我们在mdx小鼠的另外三株mdx（2cv）、mdx（4cv）和mdx（5cv）等位基因中发现突变，mdx（2cv）小鼠的突变是抗营养不良蛋白内含子42剪接受体序列的单碱基变化，该突变导致复杂的异常剪接模式，产生多个转录本，其中没有一个保留正常的开放阅读框。在mdx（5cv）等位基因中，抗营养不良蛋白mRNA含有53 bp的外显子10序列缺失。对基因组DNA的分析发现，在第10号外显子有一个单一的a到T的翻转，虽然这种碱基的变化不会改变编码的氨基酸，但在加工的mRNA中产生了一个新的剪接供体（GTGAG），产生了一个移框缺失。在mdx（4cv）等位基因中，直接测序显示在第53号外显子中有一个C到T的转变，产生了一个褐色密码子（CAA到TAA）。这些突变相对于七个已知的肌营养不良蛋白启动子的不同位置导致了一系列mdx小鼠突变体在其同种异构体表达方面的差异，因此这些小鼠应该对肌营养不良蛋白表达和功能的研究有用。mdx（4cv）和mdx（5cv）菌株由于其突变逆转的频率较低，可能在基因转移研究中有额外的用途。
Mutations in the dystrophin gene are responsible for Duchenne and Becker muscular dystrophy (DMD/BMD), Studies of dystrophin expression and function have benefited from use of the mdx mouse, an animal model for DMD/BMD. Here we characterized mutations in three additional strains of mdx mice, the mdx(2cv), mdx(4cv) and mdx(5cv) alleles, The mutation in the mdx(2cv) mouse was found to be a single base change in the splice acceptor sequence of dystrophin intron 42, This mutation leads to a complex pattern of aberrant splicing that generates multiple transcripts, none of which preserve the normal open reading frame, In the mdx(5cv) allele, the dystrophin mRNA contains a 53 bp deletion of sequences from exon 10, Analysis of the genomic DNA uncovered a single A to T transversion in exon 10, Although this base change does not alter the encoded amino acid, a new splice donor was created (GTGAG) that generates a frameshifting deletion in the processed mRNA, In the mdx(4cv) allele, direct sequencing revealed a C to T transition in exon 53, creating an ochre codon (CAA to TAA), The differential location of these mutations relative to the seven known dystrophin promoters results in a series of mdx mouse mutants that differ in their repertoire of isoform expression, such that these mice should be useful for studies of dystrophin expression and function. The mdx(4cv) and mdx(5cv) strains may be of additional use in gene transfer studies due to their low frequency of mutation reversion.