DSCR1 (ADAPT78) lethality: Evidence for a protective effect of trisomy 21 genes?

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.