Facial reconstruction

Search LJMU Research Online

Browse Repository | Browse E-Theses

A Mutation in the Mitochondrial Fission Gene Dnm1l Leads to Cardiomyopathy

Ashrafian, H, Docherty, L, Leo, V, Towlson, C, Neilan, M, Steeples, V, Lygate, CA, 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, JL , Hargreaves, IP, Fernandez-Fuentes, N, Cheeseman, M, Watkins, H and Dear, TN (2010) A Mutation in the Mitochondrial Fission Gene Dnm1l Leads to Cardiomyopathy. PLoS Genetics, 6 (6). ISSN 1553-7404

[img]
Preview
Text
A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy.pdf - Published Version
Available under License Creative Commons Attribution.

Download (7MB) | Preview

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.

Item Type: Article
Uncontrolled Keywords: 0604 Genetics
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Public Library of Science
Related URLs:
Date Deposited: 22 Sep 2020 10:39
Last Modified: 22 Sep 2020 10:45
DOI or Identification number: 10.1371/journal.pgen.1001000
URI: https://researchonline.ljmu.ac.uk/id/eprint/13686

Actions (login required)

View Item View Item