Genetics research has made outstanding contributions to our understanding of mammalian gene function, human genetics and disease. Our group studies a variety of genetic diseases using a model system, aiming to identify new disease alleles, as well as elucidating gene function. One example is heart disease, a major health concern due to its high prevalence, morbidity and mortality. A leading cause of congestive heart failure is dilated cardiomyopathy (DCM). Mutations in a variety of genes have been associated with dilated cardiomyopathy (DCM), however such mutations account for only a small proportion of cases of familial DCM emphasizing the need for alternative discovery approaches to uncover other pathogenic mutations. As part of a large-scale N-ethyl-N-nitrosourea screen, a variant, was detected – named Python - that develops severe DCM due to a dominant fully penetrant mutation in a gene called Dnm1l, which is known to be critical for normal mitochondrial and peroxisomal fission. Indeed fibroblasts with this mutation have elongated mitochondria and peroxisomes (Figure 1). The viable heterozygotes exhibit severe and rapidly progressive cardiac ATP depletion (Figure 2). The resulting energy deficiency contributes to, and may be the proximate cause of, cardiomyopathy. This disease model reveals the importance of mitochondrial remodelling in the heart. With our collaborators in Oxford (Houman Ashrafian and Hugh Watkins) and Leeds (Chris Peers and John Boyle) we are investigating the metabolic phenotype that results from the Python mutation and how this might lead to cardiac remodelling and, ultimately, heart failure.
Figure 1: Mitochondria (stained red) and peroxisomes (green) in normal fibroblasts (+ /+) and those containing the Python mutation (Py / +)
Figure 2: ATP levels seen in various tissues with and without the Python mutation. Note the drastic reduction in the heart (**)
Another example where the balance between mitochondrial fusion and fission is perturbed is Huntington’s Disease (HD). HD is accompanied by numerous changes in mitochondria. This includes alterations in morphology, in particular fragmentation and cristae remodeling, which are linked to an increased susceptibility to apoptosis. Levels of Dnm1l are elevated in HD, and the mutant Htt protein enhances Dnm1l activity. Inhibiting the activity of Drp1 can correct both the abnormal fission and resulting apoptosis. We are presently investigating whether altering activity of mitochondrial fusion and fission factors in vivo can ameliorate the neurodegeneration and accompanying disease symptoms.
Miller G, Neilan M, Chia R, Gheryani N, Holt N, Charbit A, Wells S, Tucci V, Lalanne Z, Denny P, Fisher EM, Cheeseman M, Askew GN & Dear TN (2010) ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2. PLoS One 5:e9137.
Ashrafian H, Docherty L, Leo V, Towlson C, Neilan M, Steeples V, Lygate C, 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 J, Hargreaves I, Fernandez-Fuentes N, Cheeseman M, Watkins H & Dear T (2010) A mutation in the mitochondrial fission-related gene Dnm1l leads to cardiomyopathy. PLoS Genetics, 6, 1-18
Williamson C, Ball S, Dawson C, Mehta S, Beechey C, Fray M, Teboul L, Dear T, Kelsey G & Peters J (2011) Uncoupling Antisense-Mediated Silencing and DNA Methylation in the Imprinted Gnas Cluster. PLoS Genetics, 7(3):e1001347.