Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression.
Nat Genet
; 21(1): 133-7, 1999 Jan.
Article
en En
| MEDLINE
| ID: mdl-9916807
ABSTRACT
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.
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Bases de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Proteínas Virales
/
ADN Mitocondrial
/
Proteínas Nucleares
/
Proteínas del Grupo de Alta Movilidad
/
Cardiomiopatía Dilatada
/
Transactivadores
/
Regulación de la Expresión Génica
/
Proteínas de Xenopus
/
Proteínas Mitocondriales
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Nat Genet
Asunto de la revista:
GENETICA MEDICA
Año:
1999
Tipo del documento:
Article
País de afiliación:
Suecia