NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21

Joseph R. Arron, Monte M. Winslow, Alberto Polleri, Ching-Pin Chang, Hai Wu, Xin Gao, Joel R. Neilson, Lei Chen, Jeremy J. Heit, Seung K. Kim, Nobuyuki Yamasaki, Tsuyoshi Miyakawa, Uta Francke, Isabella A. Graef () and Gerald R. Crabtree ()
Additional contact information
Joseph R. Arron: Department of Pathology
Monte M. Winslow: Program in Immunology
Alberto Polleri: Department of Pathology
Ching-Pin Chang: Division of Cardiovascular Medicine, Department of Medicine
Hai Wu: Department of Pathology
Xin Gao: Department of Pathology
Joel R. Neilson: Program in Immunology
Lei Chen: Department of Pathology
Jeremy J. Heit: Department of Developmental Biology
Seung K. Kim: Department of Developmental Biology
Nobuyuki Yamasaki: Genetic Engineering and Functional Genomics Unit, HMRO, Kyoto University Graduate School of Medicine
Tsuyoshi Miyakawa: Genetic Engineering and Functional Genomics Unit, HMRO, Kyoto University Graduate School of Medicine
Uta Francke: Department of Genetics
Isabella A. Graef: Department of Pathology
Gerald R. Crabtree: Department of Pathology

Nature, 2006, vol. 441, issue 7093, 595-600

Abstract: Abstract 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.

Date: 2006
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DOI: 10.1038/nature04678

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