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Lookup NU author(s): Professor David Samuels, Professor Patrick Chinnery
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Mitochondrial medicine is one of the few areas of genetic disease where germ-line transfer is being actively pursued as a treatment option. All of the germ-line transfer methods currently under development involve some carry-over of the maternal mitochondrial DNA (mtDNA) heteroplasmy, potentially delivering the pathogenic mutation to the offspring. Rapid changes in mtDNA heteroplasmy have been observed within a single generation, and so any oleakage' of mutant mtDNA could lead to mtDNA disease in future generations, compromising the reproductive health of the first generation, and leading to repeated interventions in subsequent generations. To determine whether this is a real concern, we developed a model of mtDNA heteroplasmy inheritance by studying 87 motherchild pairs, and predicted the likely outcome of different levels of omutant mtDNA leakage' on subsequent maternal generations. This showed that, for a clinical threshold of 60, reducing the proportion of mutant mtDNA to 5 dramatically reduces the chance of disease recurrence in subsequent generations, but transmitting 5 mutant mtDNA was associated with a significant chance of disease recurrence. Mutations with a lower clinical threshold were associated with a higher risk of recurrence. Our findings provide reassurance that, at least from an mtDNA perspective, methods currently under development have the potential to effectively eradicate pathogenic mtDNA mutations from subsequent generations.
Author(s): Samuels DC, Wonnapinij P, Chinnery PF
Publication type: Article
Publication status: Published
Journal: Human Reproduction
Year: 2013
Volume: 28
Issue: 3
Pages: 554-559
Print publication date: 07/01/2013
ISSN (print): 0268-1161
ISSN (electronic): 1460-2350
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/humrep/des439
DOI: 10.1093/humrep/des439
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