1. Department of Pathology,
2. Program in Immunology,
3. Division of Cardiovascular Medicine, Department of Medicine,
4. Department of Developmental Biology,
5. Department of Genetics and
6. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA
7. Genetic Engineering and Functional Genomics Unit, HMRO, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
8. *These authors contributed equally to this work

Correspondence to: Isabella A. Graef^1,8Gerald R. Crabtree^1,4,6 Correspondence and requests for materials should be addressed to G.R.C. (Email: crabtree@stanford.edu) or I.A.G. (Email: igraef@stanford.edu).

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.

1. Department of Pathology,
2. Program in Immunology,
3. Division of Cardiovascular Medicine, Department of Medicine,
4. Department of Developmental Biology,
5. Department of Genetics and
6. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA
7. Genetic Engineering and Functional Genomics Unit, HMRO, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
8. *These authors contributed equally to this work

Correspondence to: Isabella A. Graef^1,8Gerald R. Crabtree^1,4,6 Correspondence and requests for materials should be addressed to G.R.C. (Email: crabtree@stanford.edu) or I.A.G. (Email: igraef@stanford.edu).

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