Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss

Hasbaira Bolor, Terumi Mori, Sachie Nishiyama, Yoshimasa Ito, Eriko Hosoba, Hidehito Inagaki, Hiroshi Kogo, Tamae Oe, Makiko Tsutsumi, Takema Kato, Maoqing Tong, Haruki Nishizawa, Kanako Pryor-Koishi, Eri Kitaoka, Tomio Sawada, Yukio Nishiyama, Yasuhiro Udagawa, Hiroki Kurahashi

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)14-20
Number of pages7
JournalAmerican Journal of Human Genetics
Volume84
Issue number1
DOIs
Publication statusPublished - 09-01-2009

Fingerprint

Synaptonemal Complex
Pregnancy
Mutation
Genes
Chromosome Pairing
Prophase
Habitual Abortion
Azoospermia
Chromosome Segregation
Chromatids
Essential Genes
Meiosis
Aneuploidy
Mutant Proteins
Chromosome Aberrations
Sex Characteristics
Genetic Recombination
Siblings
Proteins
Fetus

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Bolor, Hasbaira ; Mori, Terumi ; Nishiyama, Sachie ; Ito, Yoshimasa ; Hosoba, Eriko ; Inagaki, Hidehito ; Kogo, Hiroshi ; Oe, Tamae ; Tsutsumi, Makiko ; Kato, Takema ; Tong, Maoqing ; Nishizawa, Haruki ; Pryor-Koishi, Kanako ; Kitaoka, Eri ; Sawada, Tomio ; Nishiyama, Yukio ; Udagawa, Yasuhiro ; Kurahashi, Hiroki. / Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss. In: American Journal of Human Genetics. 2009 ; Vol. 84, No. 1. pp. 14-20.
@article{934f13cec09a4c71a678fcaf5d92e321,
title = "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.",
author = "Hasbaira Bolor and Terumi Mori and Sachie Nishiyama and Yoshimasa Ito and Eriko Hosoba and Hidehito Inagaki and Hiroshi Kogo and Tamae Oe and Makiko Tsutsumi and Takema Kato and Maoqing Tong and Haruki Nishizawa and Kanako Pryor-Koishi and Eri Kitaoka and Tomio Sawada and Yukio Nishiyama and Yasuhiro Udagawa and Hiroki Kurahashi",
year = "2009",
month = "1",
day = "9",
doi = "10.1016/j.ajhg.2008.12.002",
language = "English",
volume = "84",
pages = "14--20",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

Bolor, H, Mori, T, Nishiyama, S, Ito, Y, Hosoba, E, Inagaki, H, Kogo, H, Oe, T, Tsutsumi, M, Kato, T, Tong, M, Nishizawa, H, Pryor-Koishi, K, Kitaoka, E, Sawada, T, Nishiyama, Y, Udagawa, Y & Kurahashi, H 2009, 'Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss', American Journal of Human Genetics, vol. 84, no. 1, pp. 14-20. https://doi.org/10.1016/j.ajhg.2008.12.002

Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss. / Bolor, Hasbaira; Mori, Terumi; Nishiyama, Sachie; Ito, Yoshimasa; Hosoba, Eriko; Inagaki, Hidehito; Kogo, Hiroshi; Oe, Tamae; Tsutsumi, Makiko; Kato, Takema; Tong, Maoqing; Nishizawa, Haruki; Pryor-Koishi, Kanako; Kitaoka, Eri; Sawada, Tomio; Nishiyama, Yukio; Udagawa, Yasuhiro; Kurahashi, Hiroki.

In: American Journal of Human Genetics, Vol. 84, No. 1, 09.01.2009, p. 14-20.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss

AU - Bolor, Hasbaira

AU - Mori, Terumi

AU - Nishiyama, Sachie

AU - Ito, Yoshimasa

AU - Hosoba, Eriko

AU - Inagaki, Hidehito

AU - Kogo, Hiroshi

AU - Oe, Tamae

AU - Tsutsumi, Makiko

AU - Kato, Takema

AU - Tong, Maoqing

AU - Nishizawa, Haruki

AU - Pryor-Koishi, Kanako

AU - Kitaoka, Eri

AU - Sawada, Tomio

AU - Nishiyama, Yukio

AU - Udagawa, Yasuhiro

AU - Kurahashi, Hiroki

PY - 2009/1/9

Y1 - 2009/1/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=58149133511&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149133511&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2008.12.002

DO - 10.1016/j.ajhg.2008.12.002

M3 - Article

VL - 84

SP - 14

EP - 20

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -