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Human polar body transfer eliminates the transmission of inherited mitochondrial DNA variants

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86650 | GEO | 2016/09/11

SECONDARY ACCESSION(S): PRJNA342524

REPOSITORIES: GEO

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Human polar body transfer eliminates the transmission of inherited mitochondrial DNA variants [methylation]

Project description:Although polar body transfer (PBT) has the potential to prevent the transmission of inherited mitochondrial DNA (mtDNA) diseases, the PBT technique is still at an early stage, as no human data are publicly available for PBT. Here, we investigated the comparative values of first and second PBT (PB1T, PB2T), spindle-chromosome and pronuclear transfer (ST, PNT), modified ST and PNT (mST and mPNT) to explore the efficiency and safety of these approaches. A comparative analysis confirmed that PB1T, mST, PB2T and mPNT could be used to donate mtDNA without resulting in significant heteroplasmy or alterations in the methylation profile and gene expression. Importantly, PB1T produced reconstructed embryos and embryonic stem cells (ESCs) in every generation with undetectable donor mtDNA. However, donor mtDNA seems to have a tendency to be amplified in generations of mPNT-ESCs with up to 3% heteroplasmy. These results suggest that PB1T holds great potential in eliminating mtDNA variants.

2016-09-11 | GSE86648 | GEO

Human polar body transfer eliminates the transmission of inherited mitochondrial DNA variants [mRNA]

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Human polar body transfer eliminates the transmission of inherited mitochondrial DNA variants

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Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants.

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DNA methylation data from ESCs derived by polar body transfer reconstructed embryos (PBTESCs)

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Elimination of mitochondrial DNA variants by nuclear genome transfer in human oocytes.

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Towards therapeutic application of pronuclear transfer to prevent transmission of mitochondrial DNA disease

Project description:Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases. Assisted reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable women who carry mtDNA mutations to have a genetically related child with a greatly reduced risk of disease. Here we report for the first time that pronuclear transplantation (PNT) between normally fertilised human zygotes provides an effective approach to preventing transmission of mtDNA disease. We found that the procedures previously used to perform PNT between abnormally fertilized human zygotes are highly inefficient when applied to those that undergo normal fertilization. We have therefore developed an alternative approach based on transplanting PN shortly after completion of the second meiotic division rather than shortly before onset of the first mitosis. This approach promotes highly efficient development to the blastocyst stage without affecting nuclear genome integrity. Furthermore, the expression profile of genes encoded by the nuclear and mitochondrial genomes was indistinguishable from unmanipulated control embryos. Importantly, levels of mtDNA transferred with the nuclear genome are below the threshold for mtDNA disease. Together these data indicate that transplantation of pronuclei early in the first cell cycle holds promise as a safe and effective approach to preventing transmission of mtDNA disease.

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