A Mutation in the Mitochondrial Fission Gene Dnm1l Leads to Cardiomyopathy

Houman Ashrafian, Louise Docherty, Vincenzo Leo, Christopher Towlson, Monica Neilan, Violetta Steeples, Craig Lygate, Tertius Hough, Stuart Townsend, Debbie Williams, Sara Wells, Dominic Norris, Sarah Glyn-Jones, John Land, Ivana Barbaric, Zuzanne Lalanne, Paul Denny, Dorota Szumska, Shoumo Bhattacharya, Julian GriffinIain Hargreaves, Narcis Fernandez-Fuentes, Michael Cheeseman, Hugh Watkins, Terence Dear

    Research output: Contribution to journalArticlepeer-review

    88 Citations (Scopus)

    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-Nnitrosourea 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.

    Original languageEnglish
    Pages (from-to)1-18
    Number of pages18
    JournalPloS Genetics
    Volume6
    Issue number6
    DOIs
    Publication statusPublished - Jun 2010

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