Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.
J Hum Genet. 2018 Apr;63(4):425-430. doi: 10.1038/s10038-018-0410-6. Epub 2018 Feb 13.
Recurrent pregnancy loss is newly defined as more than two consecutive miscarriages. Recurrent pregnancy loss occurs in <5% of total pregnancies. The cause in approximately 40-60% of recurrent pregnancy loss cases remains elusive and must be determined. We investigated two unrelated Iranian consanguineous families with recurrent pregnancy loss. We performed exome sequencing using DNA from a miscarriage tissue and identified a homozygous NOP14 missense variant (c.[136C>G];[136C>G]) in both families. NOP14 is an evolutionally conserved protein among eukaryotes and is required for 18S rRNA processing and 40S ribosome biogenesis. Interestingly, in zebrafish, homozygous mutation of nop14 (possibly loss of function) resulting from retrovirus-mediated insertional mutagenesis led to embryonic lethality at 5 days after fertilization, mimicking early pregnancy loss in humans. Similarly, it is known that the nop14-null yeast is inviable. These data suggest that the homozygous NOP14 mutation is likely to cause recurrent pregnancy loss. Furthermore, this study shows that exome sequencing is very useful to determine the etiology of unsolved recurrent pregnancy loss.
复发性妊娠丢失被新定义为两次以上连续流产。复发性妊娠丢失发生在<5%的总妊娠中。约 40-60%的复发性妊娠丢失病例的原因仍不清楚，必须确定。我们研究了两个无关的伊朗近亲家庭的复发性妊娠丢失。我们使用流产组织中的 DNA 进行外显子组测序，在两个家庭中均发现 NOP14 错义变异的纯合子（c.[136C>G];[136C>G]）。NOP14 是真核生物中进化保守的蛋白质，是 18S rRNA 加工和 40S 核糖体生物发生所必需的。有趣的是，在斑马鱼中，由于逆转录病毒介导的插入诱变导致 nop14 纯合突变（可能失去功能），导致受精后 5 天胚胎致死，类似于人类的早期妊娠丢失。同样，已知 nop14 缺失酵母是不能存活的。这些数据表明，NOP14 突变的纯合子很可能导致复发性妊娠丢失。此外，这项研究表明，外显子组测序非常有助于确定未解决的复发性妊娠丢失的病因。
