Kanako Pryor-Koishi

Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss

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 I. 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.

Increased levels of pregnancy-associated plasma protein-A2 in the serum of pre-eclamptic patients

Pregnancy-associated plasma protein-A and -A2 (PAPP-A and -A2) are proteases that cleave insulin-like growth factor-binding proteins (IGFBPs), resulting in local activation of IGF signaling pathways. Here, we examined PAPP-A and -A2 mRNA and protein levels in placenta and maternal sera from women with pre-eclampsia and compared them with samples from uncomplicated pregnancy. PAPP-A2 but not PAPP-A mRNA and protein were elevated in pre-eclamptic placenta (P < 0.01). PAPP-A2 is normally produced in placental syncytiotrophoblast cells and maternal decidua. PAPP-A2 in syncytiotrophoblast cells was dramatically increased in pre-eclampsia. Maternal serum concentrations of PAPP-A2 but not PAPP-A were also significantly elevated in pre-eclampsia as compared with uncomplicated pregnancy. mRNA levels of IGFBP5, a specific substrate for PAPP-A2 protease activity, were also significantly increased, suggesting a potential role for IGFBP5 in fetal and placental growth suppression during pre-eclampsia. However, IGFBP5 protein levels were not increased in placenta from pre-eclampsia, possibly due to cleavage by up-regulated PAPP-A2. These data might imply that PAPP-A2 may be up-regulated in pre-eclamptic pregnancy to compensate for IGFBP5-mediated suppression of the IGF pathway, although final birthweights are still low in pre-eclamptic pregnancy.

Overproduction of the follistatin‐related gene protein in the placenta and maternal serum of women with pre‐eclampsia

Objective  To characterise the follistatin‐related gene (FLRG) in pre‐eclampsia, one of the differentially expressed genes in pre‐eclamptic placenta.

Analysis of Nitric Oxide Metabolism as a Placental or Maternal Factor Underlying the Etiology of Pre-Eclampsia

Background:Defective nitric oxide (NO)-mediated vasodilation is widely regarded as an underlying cause of hypertension in pre-eclampsia, although there are also arguments against this hypothesis. Methods:We examined both the mRNA levels and the presence of a Glu298Asp substitution in the NO synthase (NOS) gene, as well as the NO metabolite concentration, in placentas and maternal sera from women with pre-eclampsia and in normotensive pregnant controls (25–40 vs. 24–41 weeks of gestation). Results:Pre-eclamptic and control placentas did not show any significant differences in their NO metabolite levels or their NOS expression levels as measured by quantitative RT-PCR. In addition, we did not find any association between pre-eclampsia and the occurrence of the Glu298Asp amino acid substitution in the NOS gene. In contrast, high maternal circulating NO metabolites were evident in severe pre-eclampsia (p < 0.0001). Although a positive correlation between circulating NO metabolites and blood pressure was not observed, uterine artery resistance measured by ultrasound was found to positively correlate with the maternal NO levels. Conclusions:Our current data suggest that an altered placental NOS pathway is unlikely to be the primary cause of pre-eclampsia and that the activation of this pathway is possibly in response to maternal symptoms.

Genetic Variation in the Indoleamine 2,3‐Dioxygenase Gene in Pre‐eclampsia

Citation Nishizawa H, Kato T, Ota S, Nishiyama S, Pryor‐Koishi K, Suzuki M, Tsutsumi M, Inagaki H, Kurahashi H, Udagawa Y. Genetic variation in the indoleamine 2,3‐Dioxygenase gene in pre‐eclampsia. Am J Reprod Immunol 2010; 64: 68–76

CD9 Gene Variations Are Not Associated with Female Infertility in Humans

Background/Aims: To determine whether genetic alterations in the CD9 gene are associated with female infertility in humans. Methods: We sequenced the entire coding region of this gene in 86 Japanese women with unexplained infertility and further conducted a case-control study of six tagging single nucleotide polymorphisms (SNPs) in this gene using an additional 164 samples obtained from a fertile control group. Results: No disease-causing mutation in the CD9 gene was evident in these samples and no significant association between the tagging SNPs and the studied cohort was identified. Conclusions: Our findings do not support the hypothesis that genetic alterations of the CD9 gene cause female infertility in humans.