Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss
Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss
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DOI：
10.1016/j.ajhg.2008.12.002
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发表时间：
2009-01-09
影响因子：
9.8
通讯作者：
Kurahashi, Hiroki
中科院分区：
文献类型：
--
作者：
Bolor, Hasbaira;Mori, Terumi;Kurahashi, Hiroki
非整倍体是一种在胚胎或胎儿中发生的染色体数目异常，至少在所有妊娠中发生5%，是人类早期妊娠丢失的主要原因。现在越来越多的证据表明，染色体的正确分离受到减数分裂1前期发生的事件的影响，这些事件包括同源染色体配对、姐妹染色单体聚集和减数分裂重组。在我们目前的研究中，我们表明SYCP3基因的突变与反复妊娠丢失有关，SYCP3基因编码同源染色体相互作用的联会复合体的重要组成部分。在26名原因不明的反复妊娠丢失的妇女中，有两人被发现携带该基因的独立杂合核苷酸变化，这在150名生育妇女中都不存在。对携带这两种突变的迷你基因的转录本的分析表明，这两种突变都影响了正常的剪接，可能导致了C末端突变蛋白的产生。突变蛋白被发现在体外与野生型蛋白相互作用，并在异源系统中共表达时抑制SYCP3蛋白的正常纤维形成。这些数据表明，这些突变可能会以显性-负性的方式产生异常的联会复合体，并导致染色体行为异常，从而可能导致反复流产。再加上之前在两名患有无精子症的男性中发现了类似的突变，我们目前的数据表明，即使在人类中也会发生对减数分裂中断做出反应的性别二型性。
Aneuploidy, a chromosomal numerical abnormality in the conceptus or fetus, occurs in at least 5% of all pregnancies and is the leading cause of early pregnancy loss in humans. Accumulating evidence now suggests that the correct segregation of chromosomes is affected by events occurring in prophase during meiosis 1. These events include homologous chromosome pairing, sister-chromatid cohesion, and meiotic recombination. In our current study, we show that mutations in SYCP3, a gene encoding an essential component of the synaptonemal complex that is central to the interaction of homologous chromosomes, are associated with recurrent pregnancy loss. Two out of 26 women with recurrent pregnancy loss of unknown cause were found to carry independent heterozygous nucleotide alterations in this gene, neither of which was present among a group of 150 fertile women. Analysis of transcripts from minigenes harboring each of these two mutations revealed that both affected normal splicing, possibly resulting in the production of C-terminally mutated proteins. The mutant proteins were found to interact with their wild-type counterpart in vitro and inhibit the normal fiber formation of the SYCP3 protein when coexpressed in a heterologous system. These data suggest that these mutations are likely to generate an aberrant synaptonemal complex in a dominant-negative manner and contribute to abnormal chromosomal behavior that might lead to recurrent miscarriage. Combined with the fact that similar mutations have been previously identified in two males with azoospermia, our current data suggest that sexual dimorphism in response to meiotic disruption occurs even in humans.