NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.
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.
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Joseph R
JR
Arron
Monte M
MM
Winslow
Alberto
A
Polleri
Ching-Pin
CP
Chang
Hai
H
Wu
Xin
X
Gao
Joel R
JR
Neilson
Lei
L
Chen
Jeremy J
JJ
Heit
Seung K
SK
Kim
Nobuyuki
N
Yamasaki
Tsuyoshi
T
Miyakawa
Uta
U
Francke
Isabella A
IA
Graef
Gerald R
GR
Crabtree
D000818:Animals; D002135:Calcium-Binding Proteins; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D050778:NFATC Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D019076:Transgenes / Q000235:genetics; D000097603:Dyrk Kinases
D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C511512:DSCR1 protein, mouse