Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
    • Publication Information:
      Publication: Basingstoke : Nature Publishing Group
      Original Publication: London, Macmillan Journals ltd.
    • Subject Terms:
      Nuclear Transfer Techniques*; DNA, Mitochondrial/*genetics ; Mitochondrial Diseases/*genetics ; Mitochondrial Diseases/*prevention & control ; Mitochondrial Replacement Therapy/*methods; Adult ; Blastocyst/cytology ; Blastocyst/metabolism ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Cytoplasm/genetics ; Cytoplasm/metabolism ; DNA, Mitochondrial/analysis ; Female ; Gene Expression Profiling ; Humans ; Male ; Meiosis ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Diseases/pathology ; Stem Cells/cytology ; Stem Cells/metabolism ; Translational Research, Biomedical ; Young Adult ; Zygote/cytology ; Zygote/metabolism
    • Abstract:
      Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases. 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 zygotes 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.
      Competing Interests: The authors declare no competing financial interests.
    • Comments:
      Erratum in: Nature. 2016 Oct 27;538(7626):542. doi: 10.1038/nature19105. (PMID: 27462813)
      Comment in: Nature. 2016 Dec 8;540(7632):210-211. doi: 10.1038/nature20483. (PMID: 27919076)
    • References:
      PLoS One. 2012;7(2):e31010. (PMID: 22393356)
      Bioinformatics. 2015 Jan 15;31(2):166-9. (PMID: 25260700)
      Genes Dev. 2015 Jun 15;29(12):1239-55. (PMID: 26109048)
      Development. 2012 Mar;139(5):829-41. (PMID: 22318624)
      Hum Reprod. 2002 Feb;17(2):407-12. (PMID: 11821286)
      Nature. 2013 Jan 31;493(7434):627-31. (PMID: 23103867)
      Bioinformatics. 2010 Jan 1;26(1):139-40. (PMID: 19910308)
      Stem Cell Rev. 2009 Jun;5(2):140-58. (PMID: 19521804)
      Mol Hum Reprod. 2009 Sep;15(9):531-8. (PMID: 19549764)
      J Med Genet. 2013 Feb;50(2):125-32. (PMID: 23339111)
      Hum Reprod. 2013 Mar;28(3):554-9. (PMID: 23297368)
      Cell Rep. 2012 May 31;1(5):506-15. (PMID: 22701816)
      Nature. 2013 Jan 31;493(7434):632-7. (PMID: 23254936)
      Genome Biol. 2013 Apr 25;14(4):R36. (PMID: 23618408)
      Nat Methods. 2008 Jul;5(7):621-8. (PMID: 18516045)
      Cell Rep. 2014 May 22;7(4):933-4. (PMID: 24856293)
      Cell Rep. 2014 May 22;7(4):935-7. (PMID: 24856294)
      Cell Stem Cell. 2012 Mar 2;10(3):239-40. (PMID: 22385652)
      Nature. 2010 May 6;465(7294):82-5. (PMID: 20393463)
      Hum Reprod Update. 2012 Jul;18(4):341-9. (PMID: 22456975)
      Nat Rev Genet. 2012 Dec;13(12):878-90. (PMID: 23154810)
      Fertil Steril. 2012 Nov;98(5):1236-40. (PMID: 22921075)
      Science. 1983 Jun 17;220(4603):1300-2. (PMID: 6857250)
      Stem Cells. 2015 Mar;33(3):639-45. (PMID: 25377180)
      Development. 2015 Sep 15;142(18):3151-65. (PMID: 26293300)
      PLoS Genet. 2014 Sep 18;10(9):e1004620. (PMID: 25232829)
      Fertil Steril. 2012 Sep;98(3):644-9. (PMID: 22608316)
      Genet Test. 2005 Fall;9(3):190-9. (PMID: 16225398)
      J Med Genet. 2014 Aug;51(8):553-62. (PMID: 25031024)
      Regen Med. 2007 Jul;2(4):349-62. (PMID: 17635044)
      Nucleic Acids Res. 2001 Aug 1;29(15):E74-4. (PMID: 11470889)
      Mol Hum Reprod. 2015 Jan;21(1):11-22. (PMID: 25425607)
      Nat Genet. 1999 Oct;23(2):147. (PMID: 10508508)
      Hum Fertil (Camb). 2008 Sep;11(3):131-46. (PMID: 18766953)
      Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):E3622-30. (PMID: 24003133)
      Cold Spring Harb Perspect Biol. 2013 Nov 01;5(11):a021220. (PMID: 24186072)
      Nat Genet. 2002 Feb;30(2):145-6. (PMID: 11799391)
      Cold Spring Harb Perspect Biol. 2015 Apr 01;7(4):a017970. (PMID: 25833844)
      J Med Genet. 2006 Mar;43(3):244-7. (PMID: 16155197)
      Genome Biol. 2014;15(12):550. (PMID: 25516281)
    • Grant Information:
      MR/L016354/1 United Kingdom MRC_ Medical Research Council; 096919 United Kingdom WT_ Wellcome Trust; MR/J003603/1 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust; G0601157 United Kingdom MRC_ Medical Research Council; MC_UP_1202/9 United Kingdom MRC_ Medical Research Council; United Kingdom CRUK_ Cancer Research UK
    • Accession Number:
      0 (DNA, Mitochondrial)
    • Publication Date:
      Date Created: 20160610 Date Completed: 20160701 Latest Revision: 20240610
    • Publication Date:
      20240610
    • Accession Number:
      PMC5131843
    • Accession Number:
      10.1038/nature18303
    • Accession Number:
      27281217