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Transmitochondrial mice carrying resistance to chloramphenicol on mitochondrial DNA: Developing the first mouse model of mitochondrial DNA disease

Nature Medicine volume 5, pages 957–960 (1999)Cite this article

Recent years have seen considerable advances in the description and understanding of mitochondrial DNA (mtDNA) disorders. However, progress towards therapies and prenatal diagnosis of mtDNA diseases has been severely impeded by the lack of a mouse model of mtDNA disease: direct manipulation of the mtDNA of mammals is not yet possible. There are thousands of copies of mtDNA in each cell and yet most mtDNA molecules in a single healthy human individual are usually identical (homoplasmy). In patients with mitochondrial disease, mutant mtDNA frequently co-exists with normal mtDNA (heteroplasmy). MtDNA is maternally inherited. Where there is a point mutation difference between a mother and her offspring, there may be a complete switching of mtDNA type within a single generation. There seems to be a genetic 'bottleneck' whereby a single or small number of founder mtDNA(s) populate the entire organism. Antenatal diagnosis of mtDNA diseases based on chorionic villus sampling is unreliable because it is unclear how mtDNA mutations are transmitted or segregate within families. Thus, the study of heteroplasmic pathogenic mtDNA mutants is fundamental to development of treatments and of genetic counseling in these unique diseases.

Mouse models of heteroplasmy

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Figure 1: Parent ES cells (left panel) and CAPr ES cells (right panel) stained for cytochrome oxidase activity12.
Figure 2: Percent CAPr mtDNA in tissues from chimeric mice.
Figure 3: Generation of CAPr ES cells.

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Acknowledgements

We thank I. Craig for providing the CAPr cell line; R. Gardner, F. Brook and A. Koss for supplying female ES cell lines; M. King, I. Holt, R. Capaldi, H. Jacobs and D. Kwiatkowski for comments on the manuscript; M.F.J. Cortina Borja for statistical advice; the Oxford University BMSU for help with microinjection techniques; and R.E. Moxon for support. This work was supported by the Wellcome Trust. J.P. is a Royal Society University Research Fellow.

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  1. Department of Paediatrics, Level 4, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    David R. Marchington & Joanna Poulton

  2. Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK

    David Barlow

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Correspondence to Joanna Poulton.

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Marchington, D., Barlow, D. & Poulton, J. Transmitochondrial mice carrying resistance to chloramphenicol on mitochondrial DNA: Developing the first mouse model of mitochondrial DNA disease. Nat Med 5, 957–960 (1999). https://doi.org/10.1038/11403

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