Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations

Autor: Rebecca Tippner-Hedges, Crystal Van Dyken, David Battaglia, David M. Lee, Eunju Kang, Paloma Martinez-Redondo, Karen Agaronyan, Shiyu Luo, Refik Kayali, Jun Wu, Paula Amato, Don P. Wolf, Cengiz Cinnioglu, Tomonari Hayama, Yeon-Mi Lee, Shoukhrat Mitalipov, Nuria Marti Gutierrez, Jeffrey T. Jensen, Diana Wu, Aida Platero-Luengo, Taosheng Huang, Xinjian Wang, Dmitry Temiakov, Dongmei Ji, Juan Carlos Izpisua Belmonte, Amy Koski, Susan B. Olson, Ying Li, Hong Ma, Riffat Ahmed
Rok vydání: 2016
Předmět:
Zdroj: Nature. 540:270-275
ISSN: 1476-4687
0028-0836
DOI: 10.1038/nature20592
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: