Poor Correlations in the Levels of Pathogenic Mitochondrial DNA Mutations in Polar Bodies versus Oocytes and Blastomeres in Humans
Poor Correlations in the Levels of Pathogenic Mitochondrial DNA Mutations in Polar Bodies versus Oocytes and Blastomeres in Humans
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DOI：
10.1016/j.ajhg.2011.03.010
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发表时间：
2011-04-08
影响因子：
9.8
通讯作者：
Steffann, Julie
中科院分区：
文献类型：
--
作者：
Gigarel, Nadine;Hesters, Laetitia;Steffann, Julie
由于mtDNA的量在早期胚胎中保持稳定，直到子宫着床，因此人类早期发育完全依赖于成熟卵母细胞的mtDNA库。因此，定量和定性的mtDNA缺陷都可能对卵母细胞的能力或早期胚胎发育产生负面影响。然而，在人类减数分裂过程中，突变型和野生型mtDNA分子的分离是未知的。为了研究这一点，我们比较了51个第一极体（PB）及其对应物的突变水平（1）MT-TL 1中的“MELAS”m.3243A > G突变（n = 30），（2）MT-TK中的“MERRF”m.8344A > G突变（n = 15），（3）MT-ATP 6的m.9185T > G突变（n = 6）。51个PB中有7个是无突变的，并且具有同质野生型对应物。在异质性PB中，突变负荷的测量是对应突变水平的粗略估计（R-2 = 0.52），偶尔观察到两个群体之间的高突变负荷差异（范围为-34%至+34%）。PB和它的对应物之间的MUR负载差异较高，在高度突变的PB，提示选择过程中对高度突变的细胞配子发生或早期胚胎发育。最后，个体差异之间的突变负荷PB和他们的同行使PB为基础的preconception诊断不可靠的预防mtDNA疾病的传播。在动物模型中没有观察到这种差异，他们强调需要对人类mtDNA分离进行彻底的研究。
Because the mtDNA amount remains stable in the early embryo until uterine implantation, early human development is completely dependent on the mtDNA pool of the mature oocyte. Both quantitative and qualitative mtDNA defects therefore may negatively impact oocyte competence or early embryonic development. However, nothing is known about segregation of mutant and wild-type mtDNA molecules during human meiosis. To investigate this point, we compared the mutant levels in 51 first polar bodies (PBs) and their counterpart (oocytes, blastomeres, or whole embryos), at risk of having (1) the "MELAS" m.3243A > G mutation in MT-TL1 (n = 30), (2) the "MERRF" m.8344A > G mutation in MT-TK (n = 15), and (3) the m.9185T > G mutation located in MT-ATP6 (n = 6). Seven out of 51 of the PBs were mutation free and had homoplasmic wild-type counterparts. In the heteroplasmic PBs, measurement of the mutant load was a rough estimate of the counterpart mutation level (R-2 = 0.52), and high mutant-load differentials between the two populations were occasionally observed (ranging from -34% to +34%). The mutant-load differentials between the PB and its counterpart were higher in highly mutated PBs, suggestive of a selection process acting against highly mutated cells during gametogenesis or early embryonic development. Finally, individual discrepancies in mutant loads between PBs and their counterparts make PB-based preconception diagnosis unreliable for the prevention of mtDNA disorder transmission. Such differences were not observed in animal models, and they emphasize the need to conduct thorough studies on mtDNA segregation in humans.