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DSCR1 (ADAPT78) lethality: evidence for a protective effect of trisomy 21 genes?
Kerri S Kluetzman1, Ana V Perez, Dana R Crawford
1Transgenic Facility, The Genomics Institute, Wadsworth Center, Troy, NY 12180, USA.
Abstract:
Over the last several years, suggestive evidence has accrued supporting a possible involvement for DSCR1 (ADAPT78) in Down syndrome. Toward testing this, we attempted to generate DSCR1 transgenic mice. Surprisingly, in almost every case, embryonic lethality was observed. In C57Bl/6 mice, DSCR1 human transgene was identified in developing embryos prior to lethality and up to day 9.5. Its mRNA expression was also observed and varied relative to control. In rare instances (twice) where transgenics survived to term, no mRNA expression was observed, suggesting that expression is required for lethality. This lethal phenotype contrasted with, and was surprising in light of, mouse models of Down syndrome where multiple chromosome 21 genes including Dscr1 are overexpressed and survive to term. To explain the seemingly contradictory lethal effect of DSCR1 by itself but not in combination with other trisomy genes, we propose that some trisomy genes (including DSCR1) confer lethality, but others suppress it.
Insights
DSCR1 (Down syndrome candidate region 1) gene expression in transgenic mice caused embryonic lethality. This suggests DSCR1 may confer lethality, while other Down syndrome genes might suppress it.
Area of Science:
- Genetics
- Developmental Biology
- Down Syndrome Research
Background:
- Growing evidence suggests a role for DSCR1 (Down syndrome candidate region 1) in Down syndrome.
- Previous studies indicated DSCR1 overexpression in Down syndrome mouse models, which survived to term.
Purpose of the Study:
- To investigate the role of DSCR1 in Down syndrome by generating DSCR1 transgenic mice.
- To determine the effect of DSCR1 expression on embryonic development and survival.
Main Methods:
- Generation of DSCR1 transgenic mice on a C57Bl/6 background.
- Monitoring of transgene presence and mRNA expression during embryonic development.
- Observation of embryonic lethality and survival rates.
Main Results:
- Transgenic mice exhibited a high incidence of embryonic lethality.
- DSCR1 transgene and mRNA were detected in lethal embryos up to day 9.5.
- Rare surviving transgenics showed no DSCR1 mRNA expression, indicating expression is linked to lethality.
- This lethal phenotype contrasts with existing Down syndrome mouse models.
Conclusions:
- DSCR1 expression alone appears to cause embryonic lethality in mice.
- This finding challenges previous observations in Down syndrome models.
- A hypothesis is proposed where some trisomy genes, including DSCR1, may confer lethality, while others suppress it, explaining the discrepancy.
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