Abstract
Mutations of mitochondrial DNA (mtDNA) cause several well-recognized human genetic syndromes with deficient oxidative phosphorylation1,2,3,4 and may also have a role in ageing and acquired diseases of old age5. We report here that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy to manipulate the expression of the gene encoding mitochondrial transcription factor A ( Tfam , previously named mtTFA), which regulates transcription and replication of mtDNA (Refs 6,7 ). Using a loxP -flanked Tfam allele ( TfamloxP; ref. 8 ) in combination with a cre -recombinase transgene under control of the muscle creatinine kinase promoter9,10, we have disrupted Tfam in heart and muscle. Mutant animals develop a mosaic cardiac-specific progressive respiratory chain deficiency, dilated cardiomyopathy, atrioventricular heart conduction blocks and die at 2-4 weeks of age. This animal model reproduces biochemical, morphological and physiological features of the dilated cardiomyopathy of Kearns-Sayre syndrome1,2,3,4. Furthermore, our findings provide genetic evidence that the respiratory chain is critical for normal heart function.
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Acknowledgements
N.-G.L. is supported by grants from Pharmacia-Upjohn, Swedish Medical Research Council (K98-13X-12197-02B, K98-13P-12204-02B), Magn. Bergvalls Stiftelse, Harald Jeanssons Stiftelse and Ronald McDonald Barnfond. A.O. is supported by a grant from the Swedish Medical Research Council (K97-12X-07122-12C). D.A.C. is supported by a grant from the National Institute of General Medical Sciences (R37-GM33088-28). G.S.B. is a Howard Hughes Medical Institute Associate Investigator. H.W. was supported by stipends from Drottning Silvias Barnfond and Samariten. P.T. is supported by grants from Swedish Medical Research Council (K98-14X-4764-20B) and Swedish Heart and Lung Foundation.
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Wang, J., Wilhelmsson, H., Graff, C. et al. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nat Genet 21, 133–137 (1999). https://doi.org/10.1038/5089
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DOI: https://doi.org/10.1038/5089
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