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© 1994 Oxford University Press

OTHER

Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion

J. Poulton*,, K. Morten, C. Freeman-Emmerson, C. Potter1, C. Sewry2, V. Dubowitz2, H. Kidd3, J. Stephenson4, W. Whitehouse5, F.J. Hansen6, M. Parisi7 and G. Brown8

Department of Paediatrics, University of Oxford, John Radcliffe Hospital Headington, Oxford OX3 9DU 1Nuffield Department of Medicine, University of Oxford Oxford 2Neuromuscular Unit, Royal Postgraduate Medical School DuCane, London 3Department of Neuropathology, University of Oxford Oxford 4Royal Hospital for Sick Children Glasgow 5Birmingham Children's Hospital Birmingham, UK 6Rigshospitalet, Kobenhavn Denmark 7Department of Developmental Biology, Beckman Center, Stanford University School of Medicine CA, USA 8Department of Biochemistry, University of Oxford Oxford, UK

*To whom correspondence should be addressed

Received April 22, 1994; Revised August 11, 1994; Accepted August 11, 1994

Recent studies show that patients presenting with cytochrome oxidase (COX) deficiency in infancy may have reduced mitochondrial DNA (mtDNA) in muscle. The human mitochondrial transcription factor A (h-mtTFA) may be an important regulator of both transcription and replication of mtDNA. h-mtTFA levels were investigated in cell lines which were either free of mtDNA ({varrho}0) or temporarily depleted by treatment with dideoxycytidine (ddC), and in tissue from three patients with mtDNA depletion and cytochrome oxidase deficiency. h-mtTFA was compared with other mitochondrial proteins such as pyruvate dehydrogenase and porin by Western blotting. The ratio of mtDNA and h-mtTFA mRNA to reference nuclear probes was measured by dual labelling of dot blots. The ratio of mtDNA to nuclear DNA in skeletal muscle was low in muscle in the three patients and in other tissues in one. h-mtTFA was low in cells depleted either permanently or transiently of mtDNA, and this reduction in h-mtTFA roughly paralleled mtDNA levels. Similarly, treatment of {varrho}0 cell lines with ddC induced a reduction in mtDNA as well as h-mtTFA protein. The relationship between h-mtTFA and mtDNA levels suggests that they may be causally linked. MtDNA depletion was accompanied by an increase in the level of h-mtTFA RNA in the cell lines but low levels in the patient. This suggests that either h-mtTFA regulates mtDNA levels, or that h-mtTFA expression may be regulated by a feedback mechanism initiated by MtDNA Depletion.


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