title: 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.
authors.affiliation: Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Houman
authors.initials: H
authors.lastname: Ashrafian
authors.forename: Louise
authors.initials: L
authors.lastname: Docherty
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leo
authors.forename: Christopher
authors.initials: C
authors.lastname: Towlson
authors.forename: Monica
authors.initials: M
authors.lastname: Neilan
authors.forename: Violetta
authors.initials: V
authors.lastname: Steeples
authors.forename: Craig A
authors.initials: CA
authors.lastname: Lygate
authors.forename: Tertius
authors.initials: T
authors.lastname: Hough
authors.forename: Stuart
authors.initials: S
authors.lastname: Townsend
authors.forename: Debbie
authors.initials: D
authors.lastname: Williams
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.forename: Dominic
authors.initials: D
authors.lastname: Norris
authors.forename: Sarah
authors.initials: S
authors.lastname: Glyn-Jones
authors.forename: John
authors.initials: J
authors.lastname: Land
authors.forename: Ivana
authors.initials: I
authors.lastname: Barbaric
authors.forename: Zuzanne
authors.initials: Z
authors.lastname: Lalanne
authors.forename: Paul
authors.initials: P
authors.lastname: Denny
authors.forename: Dorota
authors.initials: D
authors.lastname: Szumska
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.forename: Iain
authors.initials: I
authors.lastname: Hargreaves
authors.forename: Narcis
authors.initials: N
authors.lastname: Fernandez-Fuentes
authors.forename: Michael
authors.initials: M
authors.lastname: Cheeseman
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: T Neil
authors.initials: TN
authors.lastname: Dear
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000151:congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034281:Dynamins; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D050259:Genes, Mitochondrial; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment
chemical_list: D008869:Microtubule-Associated Proteins; D020558:GTP Phosphohydrolases; C486391:Dnm1l protein, mouse; D034281:Dynamins