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A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy
Abstract
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- Journal Article
- Amino Acid Sequence
- Animals
- Base Sequence
- Cardiomyopathy, Dilated
- Dynamins
- Embryo, Mammalian
- GTP Phosphohydrolases
- Genes, Mitochondrial
- Genetic Predisposition to Disease
- Male
- Mice
- Mice, Inbred BALB C
- Microscopy, Electron, Transmission
- Microtubule-Associated Proteins
- Models, Molecular
- Molecular Sequence Data
- Mutation
- Protein Structure, Quaternary
- Sequence Alignment
- Animals
- Mice, Inbred BALB C
- Mice
- Cardiomyopathy, Dilated
- Genetic Predisposition to Disease
- GTP Phosphohydrolases
- Dynamins
- Microtubule-Associated Proteins
- Microscopy, Electron, Transmission
- Sequence Alignment
- Amino Acid Sequence
- Base Sequence
- Protein Structure, Quaternary
- Mutation
- Models, Molecular
- Molecular Sequence Data
- Male
- Genes, Mitochondrial
- Embryo, Mammalian
- Amino Acid Sequence
- Animals
- Base Sequence
- Cardiomyopathy, Dilated
- Dynamins
- Embryo, Mammalian
- GTP Phosphohydrolases
- Genes, Mitochondrial
- Genetic Predisposition to Disease
- Male
- Mice
- Mice, Inbred BALB C
- Microscopy, Electron, Transmission
- Microtubule-Associated Proteins
- Models, Molecular
- Molecular Sequence Data
- Mutation
- Protein Structure, Quaternary
- Sequence Alignment
- Developmental Biology
- 0604 Genetics