NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21
NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21
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DOI：
10.1038/nature04678
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发表时间：
2006-06-01
期刊：
影响因子：
64.8
通讯作者：
Crabtree, Gerald R.
中科院分区：
文献类型：
--
作者：
Arron, Joseph R.;Winslow, Monte M.;Crabtree, Gerald R.
21三体导致唐氏综合征，但人们对基因剂量增加1.5倍如何产生唐氏综合征的多效性表型知之甚少。在这里，我们报告说，两个基因，DSCR1和DYRK1A，位于人类21号染色体的关键区域内，协同作用，以防止核占用NFATc转录因子，这是脊椎动物发育的调节器。我们使用数学建模来预测，该途径内的自动调节加重了DSCR1和DYRK1A的三体性的影响，导致在特定条件下无法激活NFATc靶基因。我们对钙调神经磷酸酶和Nfatc缺陷小鼠、Dym1和Dyrk1a过表达小鼠、唐氏综合征和人类21三体小鼠模型的观察与这些预测一致。我们认为，DSCR1和DYRK1A的剂量增加1.5倍，协同稳定的调节回路，导致NFATc活性降低和唐氏综合征的许多特征。更一般地说，这些观察结果表明，调节回路的不稳定可能是人类疾病的基础。
Trisomy 21 results in Down's syndrome, but little is known about how a 1.5-fold increase in gene dosage produces the pleiotropic phenotypes of Down's syndrome. Here we report that two genes, DSCR1 and DYRK1A, lie within the critical region of human chromosome 21 and act synergistically to prevent nuclear occupancy of NFATc transcription factors, which are regulators of vertebrate development. We use mathematical modelling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. Our observations of calcineurin- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down's syndrome and human trisomy 21 are consistent with these predictions. We suggest that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down's syndrome. More generally, these observations suggest that the destabilization of regulatory circuits can underlie human disease.