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.
Bolor
Hasbaira
H
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Mori
Terumi
T
Nishiyama
Sachie
S
Ito
Yoshimasa
Y
Hosoba
Eriko
E
Inagaki
Hidehito
H
Kogo
Hiroshi
H
Ohye
Tamae
T
Tsutsumi
Makiko
M
Kato
Takema
T
Tong
Maoqing
M
Nishizawa
Haruki
H
Pryor-Koishi
Kanako
K
Kitaoka
Eri
E
Sawada
Tomio
T
Nishiyama
Yukio
Y
Udagawa
Yasuhiro
Y
Kurahashi
Hiroki
H
D000026:Abortion, Habitual / Q000235:genetics*; D000328:Adult; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011247:Pregnancy; D013573:Synaptonemal Complex / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C490060:SYCP3 protein, human