Lookup NU author(s): Dr Louise Hyslop,
Dr Lyndsey Butterworth,
Dr Nilendran Prathalingam,
Dr Yuko Takeda,
Dr Helen Tuppen,
Dr Laura Irving,
Dr Meenakshi Choudhary,
Professor Alison Murdoch,
Professor Doug Turnbull,
Professor Mary Herbert
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2016.
For re-use rights please refer to the publisher's terms and conditions.
Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases1. Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof-of-concept studies involving abnormally fertilized human zygotes2 were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. After optimization, mtDNA carryover was reduced to <2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover. We conclude that PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.
Author(s): Hyslop LA, Blakeley P, Craven L, Richardson J, Fogarty NME, Fragouli E, Lamb M, Wamaitha SE, Prathalingam N, Zhang Q, OKeefe H, Takeda Y, Arizzi L, Alfarawati S, Tuppen H, Irving L, Kalleas D, Choudhary M, Wells D, Murdoch AP, Turnbull DM, Niakan KK, Herbert M
Publication type: Article
Publication status: Published
Print publication date: 16/06/2016
Online publication date: 08/06/2016
Acceptance date: 03/05/2016
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Publishing Group
PubMed id: 27281217
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