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Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression.

Mutations of mitochondrial DNA (mtDNA) cause several well-recognized human genetic syndromes with deficient oxidative phosphorylation and may also have a role in ageing and acquired diseases of old age. 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. Using a loxP-flanked Tfam allele (TfamloxP) in combination with a cre-recombinase transgene under control of the muscle creatinine kinase promoter, 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 syndrome. Furthermore, our findings provide genetic evidence that the respiratory chain is critical for normal heart function.

Pubmed ID: 9916807


  • Wang J
  • Wilhelmsson H
  • Graff C
  • Li H
  • Oldfors A
  • Rustin P
  • Brüning JC
  • Kahn CR
  • Clayton DA
  • Barsh GS
  • Thorén P
  • Larsson NG


Nature genetics

Publication Data

January 10, 1999

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R37-GM33088-28

Mesh Terms

  • Animals
  • Cardiomyopathy, Dilated
  • Creatine Kinase
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Electron Transport Complex IV
  • Female
  • Gene Expression Regulation
  • Heart
  • Heart Block
  • High Mobility Group Proteins
  • Humans
  • Integrases
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondrial Proteins
  • Muscle, Skeletal
  • Myocardium
  • NAD(P)H Dehydrogenase (Quinone)
  • Nuclear Proteins
  • Trans-Activators
  • Transcription Factors
  • Viral Proteins
  • Xenopus Proteins