Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease.
Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease.
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作者：
线粒体DNA（mtDNA）突变是母系遗传的，与广泛的衰弱和致命的疾病。旨在将线粒体DNA遗传与核DNA分离的生殖技术可能使受影响的妇女能够拥有遗传相关的孩子，并大大降低线粒体DNA疾病的风险。在这里，我们报告的第一个临床前研究原核移植（PNT）。令人惊讶的是，在涉及异常受精的人类受精卵的概念验证研究中使用的技术不能被正常受精的受精卵很好地耐受。因此，我们已经开发了一种替代方法的基础上移植原核后不久完成减数分裂，而不是前不久的第一次有丝分裂分裂。这促进了有效发育到胚泡阶段，对非整倍性或基因表达没有可检测的影响。优化后，大多数（79%）PNT囊胚的mtDNA携带率降低至<2%。将携带降低到尽可能低的水平的重要性通过来自具有4%mtDNA携带的PNT胚泡的干细胞系中异质性的逐渐增加而突出。我们的结论是，PNT有可能降低mtDNA疾病的风险，但它可能不能保证预防。
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. Following optimisation, 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.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
8.8
作者：
Lee HS;Ma H;Juanes RC;Tachibana M;Sparman M;Woodward J;Ramsey C;Xu J;Kang EJ;Amato P;Mair G;Steinborn R;Mitalipov S
通讯作者：
Mitalipov S
影响因子：
6.7
作者：
Forman, Eric J.;Li, Xinying;Scott, Richard T., Jr.
通讯作者：
Scott, Richard T., Jr.
影响因子：
4.6
作者：
Niakan, Kathy K.;Han, Jinnuo;Pera, Renee A. Reijo
通讯作者：
Pera, Renee A. Reijo
影响因子：
4
作者：
Burgstaller JP;Johnston IG;Poulton J
通讯作者：
Poulton J