Down's syndrome is caused by having three (rather than two) copies of chromosome 21, but researchers know little about how a 1.5-fold increase in gene dosage on this chromosome triggers the various developmental problems associated with Down's syndrome.
In a study published online by Nature, Gerald Crabtree and his colleagues make an important step towards answering that question. They show that two genes on chromosome 21, called DSCR1 and DYRK1A, work together to export from the cell nucleus - and reduce the activity of - a group of NFAT proteins that are critical for gene regulation during vertebrate growth and development.
The authors found that mice with mutations in Nfat genes show many of the characteristics of Down's syndrome. NFAT proteins normally operate under a positive feedback loop, enhancing their own production. The researchers used mathematical modelling and studies of genetically engineered mice to show that a 1.5-fold increase in DSCR1 and DYRK1A gene dosage produces a disproportionately large reduction in NFAT activity. The feedback loop means that an initially small reduction in NFAT grows into a larger one, leading to decreased activation of NFAT target genes.
Gerald Crabtree (Stanford University School of Medicine, Stanford, CA, USA)
Abstract available online.
(C) Nature press release.
Message posted by: Trevor M. D'Souza
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