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Comparative analysis of different nuclear transfer techniques to prevent the transmission of mitochondrial DNA variants

(2019) MOLECULAR HUMAN REPRODUCTION. 25(12). p.797-810
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Abstract
Prevention of mitochondrial DNA (mtDNA) diseases may currently be possible using germline nuclear transfer (NT). However, scientific evidence to compare efficiency of different NT techniques to overcome mtDNA diseases is lacking. Here, we performed four types of NT, including first or second polar body transfer (PB1/2T), maternal spindle transfer (ST) and pronuclear transfer (PNT), using NZB/OlaHsd and B6D2F1 mouse models. Embryo development was assessed following NT, and mtDNA carry-over levels were measured by next generation sequencing (NGS). Moreover, we explored two novel protocols (PB2T-a and PB2T-b) to optimize PB2T using mouse and human oocytes. Chromosomal profiles of NT-generated blastocysts were evaluated using NGS. In mouse, our findings reveal that only PB2T-b successfully leads to blastocysts. There were comparable blastocyst rates among PB1T, PB2T-b, ST and PNT embryos. Furthermore, PB1T and PB2T-b had lower mtDNA carry-over levels than ST and PNT. After extrapolation of novel PB2T-b to human in vitro matured (IVM) oocytes and in vivo matured oocytes with smooth endoplasmic reticulum aggregate (SERa) oocytes, the reconstituted embryos successfully developed to blastocysts at a comparable rate to ICSI controls. PB2T-b embryos generated from IVM oocytes showed a similar euploidy rate to ICSI controls. Nevertheless, our mouse model with non-mutated mtDNAs is different from a mixture of pathogenic and non-pathogenic mtDNAs in a human scenario. Novel PB2T-b requires further optimization to improve blastocyst rates in human. Although more work is required to elucidate efficiency and safety of NT, our study suggests that PBT may have the potential to prevent mtDNA disease transmission.
Keywords
POLAR BODY, EMBRYONIC-DEVELOPMENT, PRONUCLEAR TRANSFER, GENOME TRANSFER, REPLACEMENT, MUTATIONS, DIAGNOSIS, DISEASES, BIRTH, PGD, mitochondrial DNA, mtDNA disease, mtDNA heteroplasmy, germline nuclear, transfer, mouse model

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MLA
Tang, Maoxing, et al. “Comparative Analysis of Different Nuclear Transfer Techniques to Prevent the Transmission of Mitochondrial DNA Variants.” MOLECULAR HUMAN REPRODUCTION, vol. 25, no. 12, 2019, pp. 797–810.
APA
Tang, M., Guggilla, R. R., Gansemans, Y., Van der Jeught, M., Boel, A., Popovic, M., … Heindryckx, B. (2019). Comparative analysis of different nuclear transfer techniques to prevent the transmission of mitochondrial DNA variants. MOLECULAR HUMAN REPRODUCTION, 25(12), 797–810.
Chicago author-date
Tang, Maoxing, Ramesh Reddy Guggilla, Yannick Gansemans, Margot Van der Jeught, Annekatrien Boel, Mina Popovic, Panagiotis Stamatiadis, et al. 2019. “Comparative Analysis of Different Nuclear Transfer Techniques to Prevent the Transmission of Mitochondrial DNA Variants.” MOLECULAR HUMAN REPRODUCTION 25 (12): 797–810.
Chicago author-date (all authors)
Tang, Maoxing, Ramesh Reddy Guggilla, Yannick Gansemans, Margot Van der Jeught, Annekatrien Boel, Mina Popovic, Panagiotis Stamatiadis, Minerva Ferrer Buitrago, Vanessa Thys, Rudy Van Coster, Dieter Deforce, Petra De Sutter, Filip Van Nieuwerburgh, and Björn Heindryckx. 2019. “Comparative Analysis of Different Nuclear Transfer Techniques to Prevent the Transmission of Mitochondrial DNA Variants.” MOLECULAR HUMAN REPRODUCTION 25 (12): 797–810.
Vancouver
1.
Tang M, Guggilla RR, Gansemans Y, Van der Jeught M, Boel A, Popovic M, et al. Comparative analysis of different nuclear transfer techniques to prevent the transmission of mitochondrial DNA variants. MOLECULAR HUMAN REPRODUCTION. 2019;25(12):797–810.
IEEE
[1]
M. Tang et al., “Comparative analysis of different nuclear transfer techniques to prevent the transmission of mitochondrial DNA variants,” MOLECULAR HUMAN REPRODUCTION, vol. 25, no. 12, pp. 797–810, 2019.
@article{8648550,
  abstract     = {{Prevention of mitochondrial DNA (mtDNA) diseases may currently be possible using germline nuclear transfer (NT). However, scientific evidence to compare efficiency of different NT techniques to overcome mtDNA diseases is lacking. Here, we performed four types of NT, including first or second polar body transfer (PB1/2T), maternal spindle transfer (ST) and pronuclear transfer (PNT), using NZB/OlaHsd and B6D2F1 mouse models. Embryo development was assessed following NT, and mtDNA carry-over levels were measured by next generation sequencing (NGS). Moreover, we explored two novel protocols (PB2T-a and PB2T-b) to optimize PB2T using mouse and human oocytes. Chromosomal profiles of NT-generated blastocysts were evaluated using NGS. In mouse, our findings reveal that only PB2T-b successfully leads to blastocysts. There were comparable blastocyst rates among PB1T, PB2T-b, ST and PNT embryos. Furthermore, PB1T and PB2T-b had lower mtDNA carry-over levels than ST and PNT. After extrapolation of novel PB2T-b to human in vitro matured (IVM) oocytes and in vivo matured oocytes with smooth endoplasmic reticulum aggregate (SERa) oocytes, the reconstituted embryos successfully developed to blastocysts at a comparable rate to ICSI controls. PB2T-b embryos generated from IVM oocytes showed a similar euploidy rate to ICSI controls. Nevertheless, our mouse model with non-mutated mtDNAs is different from a mixture of pathogenic and non-pathogenic mtDNAs in a human scenario. Novel PB2T-b requires further optimization to improve blastocyst rates in human. Although more work is required to elucidate efficiency and safety of NT, our study suggests that PBT may have the potential to prevent mtDNA disease transmission.}},
  author       = {{Tang, Maoxing and Guggilla, Ramesh Reddy and Gansemans, Yannick and Van der Jeught, Margot and Boel, Annekatrien and Popovic, Mina and Stamatiadis, Panagiotis and Ferrer Buitrago, Minerva and Thys, Vanessa and Van Coster, Rudy and Deforce, Dieter and De Sutter, Petra and Van Nieuwerburgh, Filip and Heindryckx, Björn}},
  issn         = {{1460-2407}},
  journal      = {{MOLECULAR HUMAN REPRODUCTION}},
  keywords     = {{POLAR BODY,EMBRYONIC-DEVELOPMENT,PRONUCLEAR TRANSFER,GENOME TRANSFER,REPLACEMENT,MUTATIONS,DIAGNOSIS,DISEASES,BIRTH,PGD,mitochondrial DNA,mtDNA disease,mtDNA heteroplasmy,germline nuclear,transfer,mouse model}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{797--810}},
  title        = {{Comparative analysis of different nuclear transfer techniques to prevent the transmission of mitochondrial DNA variants}},
  url          = {{http://dx.doi.org/10.1093/molehr/gaz062}},
  volume       = {{25}},
  year         = {{2019}},
}

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