A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy.
A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy.
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DOI：
10.1371/journal.pgen.1001000
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发表时间：
2010-06-24
期刊：
影响因子：
4.5
通讯作者：
Dear TN
中科院分区：
文献类型：
--
作者：
Ashrafian H;Docherty L;Leo V;Towlson C;Neilan M;Steeples V;Lygate CA;Hough T;Townsend S;Williams D;Wells S;Norris D;Glyn-Jones S;Land J;Barbaric I;Lalanne Z;Denny P;Szumska D;Bhattacharya S;Griffin JL;Hargreaves I;Fernandez-Fuentes N;Cheeseman M;Watkins H;Dear TN
许多基因的突变与遗传性扩张型心肌病（DCM）有关。然而，这样的突变只占一小部分的临床病例，强调需要替代的发现方法来发现新的致病突变，迄今尚未确定的途径。因此，作为大规模N-乙基-N-亚硝基脲诱变筛选的一部分，我们鉴定了一种小鼠突变体Python，其发展DCM。我们证明，Python表型是由于发动蛋白-1样（Dnm 1 l）基因中的显性完全渗透突变，这已被证明是线粒体分裂的关键。的C452 F突变是在一个高度保守的区域的M结构域的Dnm 1 l，改变蛋白质的相互作用在酵母双杂交系统，这表明该突变可能会改变分子内的Dnm 1 l单体的相互作用。杂合子蟒蛇成纤维细胞表现出异常的线粒体和过氧化物酶体。突变的纯合性导致胚胎在妊娠中期死亡。杂合子蟒蛇心脏显示线粒体酶复合物水平降低，并患有心脏ATP耗竭。由此产生的能量缺乏可能导致心肌病。这是首次证明参与线粒体重塑的基因缺陷可能导致心肌病，表明该基因的功能是以相对组织特异性的方式维持正常细胞功能所必需的。这种疾病模型证明了心脏线粒体重塑的重要性;类似的缺陷可能是人类心肌疾病的基础。心脏病很常见。一些心脏病病例受到生活方式和饮食的强烈影响，而另一些病例则有很强的遗传成分。某种形式的心力衰竭，称为扩张型心肌病（DCM），通常在家庭中运行，这表明这种疾病的基因缺陷。我们描述了一种新的小鼠突变体，称为“蟒蛇”，患有类似DCM的心脏病。我们能够精确地找出导致这种疾病的缺陷基因。这种基因通常参与线粒体的分裂，线粒体是细胞的“发电厂”，为细胞产生主要的能量供应之一。这是一个独特的模型，涉及一个新的基因和疾病的机制，为进一步研究。
Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease. Heart disease is very common. Some cases of heart disease are strongly influenced by lifestyle and diet, whereas others have a strong genetic component. A certain form of heart failure, known as dilated cardiomyopathy (DCM) quite often runs in families suggesting that a defective gene or genes underlie this disease. We describe a new mouse mutant called “Python” which suffers from a heart disease similar to DCM. We were able to pinpoint the defective gene responsible for the disease. This gene is normally involved in the division of mitochondria, the “power plants” of the cell that generate one of the main energy supplies for the cell. This is a unique model that implicates a new gene and mechanism of disease for further investigation.
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影响因子：
10.8
作者：
Chen, Le;Gong, Qizhi;Knowlton, Anne A.
通讯作者：
Knowlton, Anne A.
影响因子：
64.5
作者：
Chen H;Vermulst M;Wang YE;Chomyn A;Prolla TA;McCaffery JM;Chan DC
通讯作者：
Chan DC
DOI：
10.1083/jcb.200211046
发表时间：
2003-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
通讯作者：
Chan DC
影响因子：
30.8
作者：
Graham, BH;Waymire, KG;Wallace, DC
通讯作者：
Wallace, DC
影响因子：
2.9
作者：
Gullberg, J;Jonsson, P;Moritz, T
通讯作者：
Moritz, T