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.

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.