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

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.