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Preventing the transmission of pathogenic mitochondrial DNA mutations: can we achieve long-term benefits from germ-line gene transfer?

Lookup NU author(s): Professor David Samuels, Professor Patrick Chinnery

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Abstract

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.


Publication metadata

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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Funding

Funder referenceFunder name
Association Francaise contre les Myopathies
Medical Research Council (UK) Centre for Translational Muscle Disease research
National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
EU
Newcastle University
Wellcome Trust
096919Z/11/ZWellcome Trust Centre for Mitochondrial Research

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