title: Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease.
abstract: Mutations in mitochondrial DNA (mtDNA) are a common cause of genetic disease. Pathogenic mutations in mtDNA are detected in approximately 1 in 250 live births and at least 1 in 10,000 adults in the UK are affected by mtDNA disease. Treatment options for patients with mtDNA disease are extremely limited and are predominantly supportive in nature. Mitochondrial DNA is transmitted maternally and it has been proposed that nuclear transfer techniques may be an approach for the prevention of transmission of human mtDNA disease. Here we show that transfer of pronuclei between abnormally fertilized human zygotes results in minimal carry-over of donor zygote mtDNA and is compatible with onward development to the blastocyst stage in vitro. By optimizing the procedure we found the average level of carry-over after transfer of two pronuclei is less than 2.0%, with many of the embryos containing no detectable donor mtDNA. We believe that pronuclear transfer between zygotes, as well as the recently described metaphase II spindle transfer, has the potential to prevent the transmission of mtDNA disease in humans.
authors.affiliation: Mitochondrial Research Group, Institute for Ageing and Health, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Craven
authors.forename: Helen A
authors.initials: HA
authors.lastname: Tuppen
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Greggains
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Harbottle
authors.forename: Julie L
authors.initials: JL
authors.lastname: Murphy
authors.forename: Lynsey M
authors.initials: LM
authors.lastname: Cree
authors.forename: Alison P
authors.initials: AP
authors.lastname: Murdoch
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Robert N
authors.initials: RN
authors.lastname: Lightowlers
authors.forename: Mary
authors.initials: M
authors.lastname: Herbert
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
mesh_terms: D001757:Blastomeres / Q000737:chemistry; D004272:DNA, Mitochondrial / Q000032:analysis* / Q000235:genetics*; D004622:Embryo, Mammalian / Q000737:chemistry / Q000166:cytology; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics / Q000517:prevention & control*; D053652:Nuclear Transfer Techniques; D015053:Zygote / Q000737:chemistry / Q000166:cytology
chemical_list: D004272:DNA, Mitochondrial
references.citation: Anal Biochem. 2007 Nov 1;370(1):127-9
references.pmid: 17662684
references.citation: Hum Fertil (Camb). 2006 Sep;9(3):157-69
references.pmid: 17008268
references.citation: Annu Rev Neurosci. 2008;31:91-123
references.pmid: 18333761
references.citation: Development. 1993 Nov;119(3):933-42
references.pmid: 8187648
references.citation: Ann Neurol. 2008 Jan;63(1):35-9
references.pmid: 17886296
references.citation: Cochrane Database Syst Rev. 2012 Apr 18;(4):CD004426
references.pmid: 22513923
references.citation: J Am Coll Cardiol. 2003 May 21;41(10):1786-96
references.pmid: 12767666
references.citation: Hum Reprod. 1996 Oct;11(10):2217-22
references.pmid: 8943533
references.citation: Nucleic Acids Res. 2002 Jul 15;30(14):e68
references.pmid: 12136116
references.citation: Nat Genet. 1999 Oct;23(2):147
references.pmid: 10508508
references.citation: Dev Biol. 1987 Oct;123(2):364-74
references.pmid: 2443405
references.citation: Nat Genet. 2002 Feb;30(2):145-6
references.pmid: 11799391
references.citation: Fertil Steril. 2004 Jan;81(1):73-9
references.pmid: 14711547
references.citation: Ann Neurol. 2004 Apr;55(4):478-84
references.pmid: 15048886
references.citation: N Engl J Med. 2009 Feb 5;360(6):642-4
references.pmid: 19196685
references.citation: Lancet. 2006 Jul 1;368(9529):87-9
references.pmid: 16815383
references.citation: Nucleic Acids Res. 2001 Aug 1;29(15):E74-4
references.pmid: 11470889
references.citation: Am J Hum Genet. 2003 Feb;72(2):333-9
references.pmid: 12518276
references.citation: Genetics. 1997 Feb;145(2):445-51
references.pmid: 9071597
references.citation: J Assist Reprod Genet. 2007 Jun;24(6):227-32
references.pmid: 17342424
references.citation: Zygote. 1995 Nov;3(4):357-65
references.pmid: 8730901
references.citation: N Engl J Med. 2009 Feb 5;360(6):640-2
references.pmid: 19196684
references.citation: Am J Hum Genet. 2001 Jan;68(1):238-40
references.pmid: 11085913
references.citation: Annu Rev Biochem. 2007;76:781-821
references.pmid: 17506638
references.citation: Reprod Biomed Online. 2002 May-Jun;4(3):243-7
references.pmid: 12709274
references.citation: Nature. 2009 Sep 17;461(7262):367-72
references.pmid: 19710649
references.citation: J Med Genet. 2006 Mar;43(3):244-7
references.pmid: 16155197
references.citation: Nat Rev Genet. 2005 May;6(5):389-402
references.pmid: 15861210
references.citation: Am J Hum Genet. 2008 Aug;83(2):254-60
references.pmid: 18674747
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16765-70
references.pmid: 16275929