A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy.
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.
Ashrafian
Houman
H
Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Docherty
Louise
L
Leo
Vincenzo
V
Towlson
Christopher
C
Neilan
Monica
M
Steeples
Violetta
V
Lygate
Craig A
CA
Hough
Tertius
T
Townsend
Stuart
S
Williams
Debbie
D
Wells
Sara
S
Norris
Dominic
D
Glyn-Jones
Sarah
S
Land
John
J
Barbaric
Ivana
I
Lalanne
Zuzanne
Z
Denny
Paul
P
Szumska
Dorota
D
Bhattacharya
Shoumo
S
Griffin
Julian L
JL
Hargreaves
Iain
I
Fernandez-Fuentes
Narcis
N
Cheeseman
Michael
M
Watkins
Hugh
H
Dear
T Neil
TN
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
D008869:Microtubule-Associated Proteins; D020558:GTP Phosphohydrolases; C486391:Dnm1l protein, mouse; D034281:Dynamins