Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss

Abstract

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.

Human male infertility and its genetic causes

“…The mutant proteins were found to interact with their wild‐type counterpart in vitro and to inhibit the normal fiber formation of the SYCP3 protein when coexpressed in a heterologous system. It is possible that the mutations generate an aberrant synaptonemal complex in a dominant‐negative manner and contribute to abnormal chromosomal behavior that might lead to recurrent miscarriage 17. These data suggest that mutations to SYCP3 induce azoospermia by meiotic arrest in men and recurrent pregnancy losses in women.…”

“…In 2009, it was reported that mutations in human SYCP3 are associated with recurrent pregnancy loss 17. Two out of 26 women with recurrent pregnancy losses of unknown cause were found to carry independent heterozygous nucleotide alterations in SYCP3 , neither of which was present among a group of 150 fertile women.…”

Screening of genes involved in chromosome segregation during meiosis I: in vitro gene transfer to mouse fetal oocytes

“…The tissues were then cultured for 2 days as described previously 17 except that Transwell membrane inserts (polycarbonate membrane, 24-mm diameter, 3.0-mm pore size, Corning, Corning, NY, USA) and minimum essential mediumalpha medium (Invitrogen, Carlsbad, CA, USA) containing 10% fetal bovine serum, and supplemented with penicillin and streptomycin were used. For expression in mouse spermatocytes, the plasmids were introduced into the testis by in vivo electroporation as described previously, 9 and these tissues were dissected out for immunostaining 2 days later.…”

“…14 However, ectopically expressed SYCP3 generates a loop-like structure not only in the nucleus but also in the cytoplasm in somatic cell lines, which had not correctly reflected its intrinsic localization pattern in a previous report. 9 Therefore, in our current analyses we introduced a plasmid DNA expressing FLAG-tagged SYCP3 into adult mouse testis by in vivo electroporation. The FLAG-tagged SYCP3 protein product was detectable in the nuclei of pachytene spermatocytes by Tables 2 and 3).…”

“…Approaches involving the sequencing of candidate genes have enabled the identification of a few meiotic genes that are causal for infertility or RPL. [6][7][8][9] Further analyses of these candidate genes will be necessary to better understand the genetic basis of human infertility and RPL. It is likely also that many other genes involved in meiosis in mammals, and that that remain to be identified, have a role in these disorders.…”