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Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations.
Nature. 2016 12 08; 540(7632):270-275.Nat

Abstract

Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States. Mitochondrial replacement therapies or techniques (MRT) circumventing mother-to-child mtDNA disease transmission involve replacement of oocyte maternal mtDNA. Here we report MRT outcomes in several families with common mtDNA syndromes. The mother's oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer, resulting in embryos containing >99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor-to-maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer proliferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT.

Authors+Show Affiliations

Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Department of Cell Biology School of Osteopathic Medicine, Rowan University, 2 Medical Center Drive, Stratford, New Jersey 08084, USA.Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Reproductive Medical Centre, Anhui Medical University, No 218, Jixi Rd, Shushan District, Heifei, Anhui 230022, China.IviGen Los Angeles, 406 Amapola Avenue, Suite 215, Torrance, California 90501, USA.IviGen Los Angeles, 406 Amapola Avenue, Suite 215, Torrance, California 90501, USA.Research Cytogenetics Laboratory, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.Department of Cell Biology School of Osteopathic Medicine, Rowan University, 2 Medical Center Drive, Stratford, New Jersey 08084, USA.Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Division of Reproductive &Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA. Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA. Knight Cardiovascular Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. Department of Biomedical Engineering, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27919073

Citation

Kang, Eunju, et al. "Mitochondrial Replacement in Human Oocytes Carrying Pathogenic Mitochondrial DNA Mutations." Nature, vol. 540, no. 7632, 2016, pp. 270-275.
Kang E, Wu J, Gutierrez NM, et al. Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature. 2016;540(7632):270-275.
Kang, E., Wu, J., Gutierrez, N. M., Koski, A., Tippner-Hedges, R., Agaronyan, K., Platero-Luengo, A., Martinez-Redondo, P., Ma, H., Lee, Y., Hayama, T., Van Dyken, C., Wang, X., Luo, S., Ahmed, R., Li, Y., Ji, D., Kayali, R., Cinnioglu, C., ... Mitalipov, S. (2016). Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature, 540(7632), 270-275. https://doi.org/10.1038/nature20592
Kang E, et al. Mitochondrial Replacement in Human Oocytes Carrying Pathogenic Mitochondrial DNA Mutations. Nature. 2016 12 8;540(7632):270-275. PubMed PMID: 27919073.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. AU - Kang,Eunju, AU - Wu,Jun, AU - Gutierrez,Nuria Marti, AU - Koski,Amy, AU - Tippner-Hedges,Rebecca, AU - Agaronyan,Karen, AU - Platero-Luengo,Aida, AU - Martinez-Redondo,Paloma, AU - Ma,Hong, AU - Lee,Yeonmi, AU - Hayama,Tomonari, AU - Van Dyken,Crystal, AU - Wang,Xinjian, AU - Luo,Shiyu, AU - Ahmed,Riffat, AU - Li,Ying, AU - Ji,Dongmei, AU - Kayali,Refik, AU - Cinnioglu,Cengiz, AU - Olson,Susan, AU - Jensen,Jeffrey, AU - Battaglia,David, AU - Lee,David, AU - Wu,Diana, AU - Huang,Taosheng, AU - Wolf,Don P, AU - Temiakov,Dmitry, AU - Belmonte,Juan Carlos Izpisua, AU - Amato,Paula, AU - Mitalipov,Shoukhrat, Y1 - 2016/11/30/ PY - 2016/03/14/received PY - 2016/11/02/accepted PY - 2016/12/6/pubmed PY - 2017/4/12/medline PY - 2016/12/6/entrez SP - 270 EP - 275 JF - Nature JO - Nature VL - 540 IS - 7632 N2 - Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States. Mitochondrial replacement therapies or techniques (MRT) circumventing mother-to-child mtDNA disease transmission involve replacement of oocyte maternal mtDNA. Here we report MRT outcomes in several families with common mtDNA syndromes. The mother's oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer, resulting in embryos containing >99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor-to-maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer proliferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/27919073/Mitochondrial_replacement_in_human_oocytes_carrying_pathogenic_mitochondrial_DNA_mutations_ L2 - https://doi.org/10.1038/nature20592 DB - PRIME DP - Unbound Medicine ER -