Calcineurin is the conserved target of the immunosuppressants cyclosporin A and FK506. Using the yeast two-hybrid system, a novel calcineurin binding protein, CBP1, as been identified from the pathogenic fungus Cryptococcus neoformans. CBP1 binds to calcineurin in vitro and in vivo, and FKBP12-FK506 inhibits CBP1 binding to calcineurin. Cryptococcus neoformans cbp1 mutant strains exhibit modest defects in growth under stress conditions and virulence, similar to but less severe than the phenotypes of calcineurin mutants. Saccharomyces cerevisiae mutants lacking the CBP1 homolog RCN1 are, like calcineurin mutants, sensitive to lithium cation stress. CBP1 shares a central peptide sequence motif, SPPxSPP, with related proteins in S. cerevisiae, Schizosaccharomyces pombe, Drosophila melanogaster, Caenorhabditis elegans and humans, and peptides containing this motif altered calcineurin activity in vitro. Interestingly, the human CBP1 homolog DSCR1 is encoded by the Down syndrome candidate region interval on chromosome 21, is highly expressed in the heart and central nervous system, and may play a role in calcineurin functions in heart development, neurite extension and memory (Gorlach, 2000).
Using a genetic screen in yeast, a new family of proteins conserved in fungi and animals has been identified that inhibits calcineurin function when overexpressed. Overexpression of the yeast protein Rcn1p or the human homologs DSCR1 or ZAKI-4 inhibits two independent functions of calcineurin in yeast -- the activation of the transcription factor Tcn1p and the inhibition of the H+/Ca2+ exchanger Vcx1p. Purified recombinant Rcn1p and DSCR1 binds calcineurin in vitro and inhibits its protein phosphatase activity. Signaling via calmodulin, calcineurin, and Tcn1p induces Rcn1p expression, suggesting that Rcn1p operates as an endogenous feedback inhibitor of calcineurin. Surprisingly, rcn1 null mutants exhibit phenotypes similar to those of Rcn1p-overexpressing cells. This effect may be due to lower expression of calcineurin in rcn1 mutants during signaling conditions. Thus, Rcn1p levels may fine-tune calcineurin signaling in yeast. The structural and functional conservation between Rcn1p and DSCR1 suggests that the mammalian Rcn1p-related proteins, termed calcipressins, will modulate calcineurin signaling in humans and potentially contribute to disorders such as Down Syndrome (Kingsbury, 2000).
A recently recognized gene family, conserved from yeast to humans, includes Down syndrome candidate region 1 gene (DSCR1), Adapt78 (recognized as the hamster ortholog of the DSCR1 isoform 4), ZAKI-4 (renamed DSCR1-like 1, DSCR1L1) and DSCR1L2 (a novel gene on human chromosome 1), along with yeast and C. elegans single members. The proposed family identifies are a putative single-strand nucleic acid binding domain similar to the RNA recognition motif, and a unique, highly-conserved serine-proline motif. A bioinformatics-driven molecular biology approach was used to characterize the murine members of DSCR1-like gene family. Systematic EST database search and RT-PCR allowed identification of the murine DSCR1, DSCR1L1 and DSCR1L2. The sequences of the respective protein products are of 198, 197 and 241 amino acids, respectively, and are very similar to the corresponding human proteins. The very broad expression pattern of the murine DSCR1 genes is similar to that of the human genes. Using a radiation hybrid panel, the murine DSCR1-like family members were mapped. The murine DSCR1 ortholog is located on the chromosome 16, in a region corresponding to that on human chromosome 21 just upstream of the Down syndrome candidate region. DSCR1L1 and DSCR1L2 murine genes are also located in chromosomal segments of chromosome 17 and 4, respectively, exactly corresponding to those containing the respective human homologs on chromosomes 6 and 1. Description of the mouse orthologs for DSCR1-like genes will allow knockout mice to be obtained for specific family members (Strippoli, 2000).
A conserved family of calcineurin-regulating proteins whose members have been implicated in several disease models such as Down syndrome, Alzheimer's disease, and cardiac hypertrophy has been identified in several organisms including yeast, mice, and humans. Caenorhabditis elegans rcn-1 belongs to this family of calcineurin regulators, and shows approximately 40% identity with the human homologue DSCR-1. rcn-1 is expressed in hypodermal cells, nerve cords and various neurons, vulva epithelial and muscle cells, marginal cells of the pharynx, and structures of the male tail. rcn-1 expression is upregulated by calcineurin activity. RCN-1 binds to calcineurin A from C.elegans lysate in a calcium-dependent manner, and inhibits bovine calcineurin phosphatase activity dose-dependently. In addition, overexpression of RCN-1 results in calcineurin-deficient phenotypes such as small body size, cuticle defects, fertility defects, slow growth, and serotonin-resistant egg-laying defects. Moreover, phenotypes observed in gain-of-function calcineurin mutant animals were restored to normal by RCN-1 overexpression. These results demonstrate an effective and specific inhibition of calcineurin in vitro as well as in vivo by RCN-1 (Lee, 2003).
Calcipressin 1 is an endogenous inhibitor of calcineurin, which is a serine/threonine phosphatase under the control of Ca(2+) and calmodulin. Calcipressin 1 is encoded by DSCR1, a gene on human chromosome 21 with seven exons, exons 1-4 are alternative first exons (isoforms 1-4). Calcipressin 1 isoform 1 has an N-terminal coding region longer than that previously described, and this generates a new polypeptide of 252 amino acids. This polypeptide is able to interact with calcineurin A and to inhibit NF-AT-mediated transcriptional activation. Endogenous calcipressin 1 exists as a complex together with the calcineurin A and B heterodimer. Calcipressin 1 is a phosphoprotein that increases its capacity to inhibit calcineurin when phosphorylated at the FLISPP motif, and this phosphorylation also controls the half-life of calcipressin 1 by accelerating its degradation. Additionally, further phosphorylation sites have been detected outside the FLISPP motif and these contribute to the complex phosphorylation pattern of calcipressin 1. Taking these results into consideration it is suggested that phosphorylation of calcipressin 1 is involved in the regulation of the phosphatase activity of calcineurin and can therefore act as a modulator of calcineurin-dependent cellular pathways (Genesca, 2003).
Down syndrome is one of the major causes of mental retardation and congenital heart malformations. Other common clinical features of Down syndrome include gastrointestinal anomalies, immune system defects and Alzheimer's disease pathological and neurochemical changes. The most likely consequence of the presence of three copies of chromosome 21 is the overexpression of its resident genes, a fact which must underlie the pathogenesis of the abnormalities that occur in Down syndrome. DSCR1, the product of a chromosome 21 gene highly expressed in brain, heart and skeletal muscle, is overexpressed in the brain of Down syndrome fetuses, and interacts physically and functionally with calcineurin A, the catalytic subunit of the Ca(2+)/calmodulin-dependent protein phosphatase PP2B. The DSCR1 binding region in calcineurin A is located in the linker region between the calcineurin A catalytic domain and the calcineurin B binding domain, outside of other functional domains previously defined in calcineurin A. DSCR1 belongs to a family of evolutionarily conserved proteins with three members in humans: DSCR1, ZAKI-4 and DSCR1L2. Overexpression of DSCR1 and ZAKI-4 inhibits calcineurin-dependent gene transcription through the inhibition of NF-AT translocation to the nucleus. Together, these results suggest that members of this newly described family of human proteins are endogenous regulators of calcineurin-mediated signaling pathways and as such, they may be involved in many physiological processes (Fuentes, 2000).
Calcineurin phosphatase activity regulates the nuclear localization of the nuclear factor of activated T cells (NFAT) family of transcription factors during immune challenge. Calcineurin inhibitors, such as the cyclosporin A-cyclophilin A and FK506-FKBP12 complexes, regulate this enzymatic activity noncompetitively by binding at a site distinct from the enzyme active site. A family of endogenous protein inhibitors of calcineurin was recently identified and shown to block calcineurin-mediated NFAT nuclear localization and transcriptional activation. One such inhibitor, Down Syndrome Critical Region 1 (DSCR1), functions in T cell activation, cardiac hypertrophy, and angiogenesis. A small region of DSCR1, the C-terminal 57 residues encoded by exon 7, has been identified is a potent inhibitor of calcineurin activity in vitro and in vivo (Chan, 2005).
Inhibition of the calcineurin-NFAT signalling pathway is one of the main challenges for immunosuppression therapy to avoid the severe side effects of the current anticalcineurinic drugs, cyclosporin A and FK506. The members of the calcipressin family are endogenous inhibitors of calcineurin. Two independent motifs within human calcipressin 1, the ELHA and the PxIxxT motifs, interact with calcineurin in an independent functional manner. The main finding here is that the ELHA-containing calcineurin-inhibitor CALP1 (CIC) motif is the responsible for the in vivo inhibition of calcineurin-mediated NFAT-dependent cytokine gene expression in human T cells. The identification of the CIC motif could be used as a starting point for the development of new immunosuppressive drugs for use in transplantation and autoimmune diseases (Aubereda, 2006).
The transcriptional regulation of Down syndrome critical region isoform 4 (DSCR1.4) is mediated by the calcineurin/nuclear factor of activated T cells (NFAT) pathway in neural cells. Stimuli that elicit an increase in the intracellular concentrations of calcium, such as membrane depolarization, induced de novo transcription of DSCR1.4, with mRNA expression peaking after 4 h and then declining. Action via the physiologically relevant L-type calcium channel was confirmed by blockade with nifedipine and verapamil. This calcium-dependent transcription of DSCR1.4 is inhibited by the calcineurin inhibitors cyclosporin A and FK506. Deletional analysis showed that the calcium- and calcineurin-dependent activation is mediated by the promoter region between nucleotides -350 and -166, a region that contains putative NFAT-binding motifs. Exogenous NFATc2 potently augmented the DSCR1.4 promoter transcriptional activity, and the involvement of endogenous NFAT signaling pathway in DSCR1.4 transcription was confirmed by the suppression of depolarization-inducible promoter activity with the NFAT inhibitor peptide VIVIT. Exogenous overexpression of DSCR1 protein (calcipressin 1) resulted in the inhibition of the transcription of DSCR1.4 and NFAT-dependent signaling. These findings suggest that calcineurin-dependent induction of DSCR1.4 product may represent an important auto-regulatory mechanism for the homeostatic control of NFAT signaling in neural cells (Cano, 2005).
DSCR1 acts as a negative regulator of calcineurin-mediated signaling and its transcript is overexpressed in the Down syndrome (DS) fetal brain. To evaluate the possible involvement of DSCR1 in DS, the mouse gene was cloned and its expression was analyzed in the central nervous system (CNS). Early expression of Dscr1 is detected mainly in the heart tube and in the CNS in rhombomere 4 and the pretectum. From embryonic day 14.5 onwards, Dscr1 is widely distributed in the CNS but becomes more restricted as the brain matures. Its neuronal expression pattern in the adult, preferentially in Purkinje and pyramidal cells, was confirmed by double labeling with glial fibrillary acidic protein. Although Dscr1 is present in trisomy in the Ts65Dn mouse, the adult brain expression pattern is not significantly altered. This expression pattern indicated that Dscr1 is a developmentally regulated gene involved in neurogenesis and cardiogenesis and suggests that it may contribute to the alterations observed in these organ systems in DS patients (Casas, 2001).
Calcineurin links calcium signaling to transcriptional responses in the immune, nervous and cardiovascular systems. To determine the function of the calcipressins, a family of putative calcineurin inhibitors, the calcineurin-dependent process of T cell activation was assessed in mice engineered to lack the gene encoding calcipressin 1 (Csp1). Csp1 regulates calcineurin in vivo, and genes triggered in an immune response have unique transactivation thresholds for T cell receptor stimulation. In the absence of Csp1, the apparent transactivation thresholds for all these genes are shifted because of enhanced calcineurin activity. This unbridled calcineurin activity drives Fas ligand expression, which normally requires high T cell receptor stimulation and results in the premature death of T helper type 1 cells. Thus, calcipressins modulate the pattern of calcineurin-dependent transcription, and may influence calcineurin activity beyond calcium to integrate a broad array of signals into the cellular response (Ryeom, 2003).
Although DSCR1 (Adapt78) has been associated with successful adaptation to oxidative stress and calcium stress and with devastating diseases such as Alzheimer's and Down syndrome, no rationale for these apparently contradictory findings has been tested. In fact, DSCR1 (Adapt78) has not yet been proved to provide protection against acute oxidative stress or calcium stress. This question was addressed using cross-adaptation to H2O2 and the calcium ionophore A23187, stable DSCR1 (Adapt78) transfection and overexpression in hamster HA-1 cells, 'tet-off' regulated DSCR1 (Adapt78) isoform 1 transgene expression in human PC-12 cells, and DSCR1 (Adapt78) antisense oligonucleotides to test the ability of the DSCR1 (Adapt78) protein product calcipressin 1 (a calcineurin inhibitor) to protect against oxidative stress and calcium stress. Under all conditions, resistance to oxidative stress and calcium stress increased as a function of DSCR1 (Adapt78)/calcipressin 1 expression and decreased as gene/protein expression diminished. It is concluded that cells may transiently use increased expression of the DSCR1 (Adapt78) gene product calcipressin 1 to provide short-term protection against acute oxidative stress and other calcium-mediated stresses, whereas chronic overexpression may be associated with Alzheimer's disease progression (Ermak, 2002).
The RCAN1 protein (previously called calcipressin 1 or MCIP1) binds to calcineurin, a serine/threonine phosphatase (PP2B), and inhibits its activity. Regulated overexpression of an RCAN1 transgene (this gene was previously called DSCR1 or Adapt78) also stimulates expression of the GSK-3beta kinase, which can antagonize the action of calcineurin. GSK-3beta is regulated by RCAN1 at a post-transcriptional level. In humans, high RCAN1 expression is found in the brain, where at least two mRNA isoforms have been reported. Therefore, expression of the various RCAN1 isoforms, resulting from differential splicing and alternative promotors in human brain, was further examined. At least three distinct RCAN1s were detected: RCAN1-1 Short at 31 kDa (RCAN1-1S), RCAN1-1 Long at 38 kDa (RCAN1-1 L), and RCAN1-4. Furthermore, the levels of RCAN1-1S, but not RCAN1-1 L or RCAN1-4 correlated with the levels of GSK-3beta. This suggests that RCAN1-1S might induce production of GSK-3beta in vivo. While RCAN1s can regulate calcineurin and GSK-3beta, it has also been shown that calcineurin and GSK-3beta can regulate RCAN1s. This study proposes a new model (incorporating all these findings) in which cells maintain an equilibrium between RCAN1s, calcineurin, and GSK-3beta (Ermak, 2006).
The Notch and Calcineurin/NFAT pathways have both been implicated in control of keratinocyte differentiation. Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-Jκ protein to the p21 promoter. Notch 1 activation functions also through a second Calcineurin-dependent mechanism acting on the p21 TATA box-proximal region. Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism. Besides control of the p21 gene, Calcineurin contributes significantly to the transcriptional response of keratinocytes to Notch 1 activation, both in vitro and in vivo. In fact, deletion of the Calcineurin B1 gene in the skin results in a cyclic alopecia phenotype, associated with altered expression of Notch-responsive genes involved in hair follicle structure and/or adhesion to the surrounding mesenchyme. Thus, an important interconnection exists between Notch 1 and Calcineurin-NFAT pathways in keratinocyte growth/differentiation control (Mammucari, 2005).
Levels of extra- and intra-cellular calcium play a major role in keratinocyte growth/differentiation control, and the calcium/Calmodulin-dependent phosphatase Calcineurin has been implicated in this process. Calcineurin is the only known serine/threonine phosphatase under calcium/calmodulin control. Among the proteins that are dephosphorylated as a consequence of Calcineurin activation are the nuclear factors of activated T cells (NFATs). Increased Calcineurin activity promotes the localization of NFATs to the nucleus, and its effect is counteracted by the phosphorylation of these factors by a number of both constitutive and inducible kinases such as GSK3, CK1, p38, and JNK1. Such a complexity of regulation is reflected by the fact that induction of NFAT-dependent transcription by Calcineurin activation is not immediately associated with increases in intracellular calcium levels, but requires a prolonged stimulus consistent with an oscillatory and accumulative mechanism of NFAT dephosphorylation and nuclear translocation (Mammucari, 2005).
Studies on the biological function of Calcineurin have been greatly facilitated by the use of the inhibitory drugs Cyclosporin A (CsA) and FK506. Several endogenous Calcineurin inhibitors have also been reported. Among these is Calcipressin (CALP1), also known as the DSCR1 gene product, located in the Down Syndrome Critical Region of human chromosome 21 and mouse chromosome 16. This protein binds directly to the CnA subunit and inhibits its activity. Importantly, Calcipressin gene expression is under direct positive control of Calcineurin/NFAT activity, so that this protein is thought to function as a feedback inhibitor of Calcineurin signaling, with an impact on T cell activation as well as the response to different stress stimuli in cardiac hypertrophy (Mammucari, 2005).
The function of Calcineurin has been elucidated in great detail in T cells, but has also been studied in the hematopoietic, neuronal, myogenic, and vascular systems. Calcineurin/NFAT activity has also been directly implicated in keratinocyte growth/differentiation control and, in vivo, in control of the hair cycle. Molecular analysis of the role of this pathway in keratinocytes has focused on control of p21 gene transcription. Induction of p21(WAF1/Cip1) is one of the earliest regulatory events associated with keratinocyte differentiation, contributing to withdrawal from the cell cycle. In mouse primary keratinocytes, p21 expression is induced by increased extracellular calcium, and the responsive region of the p21 promoter maps to a 78 bp GC-rich region close to the TATA box, containing six Sp1/Sp3 binding sites. Calcineurin induces activation of this promoter through the Calcineurin-dependent association of NFAT with the transcription factors Sp1/Sp3 (Mammucari, 2005).
Notch 1 activation induces p21 transcription not only through direct binding of the RBP-Jκ protein to the p21 promoter, but also through the calcium/Calcineurin-responsive TATA box-proximal region. Underlying this effect, induction of Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, in opposition to positive control of this gene by Calcineurin/NFAT itself. Besides control of p21 expression, Calcineurin signaling plays a significantly broader role in the transcriptional response of keratinocytes to Notch 1 activation. In particular, inducible deletion of the CnB1 gene in the skin causes a cyclic alopecia phenotype that is linked to altered expression of several Notch-responsive genes involved in hair follicle structure and adhesion to the surrounding mesenchyme (Mammucari, 2005).
Vascular endothelial growth factor (VEGF) is a principal stimulator of angiogenesis. However, the downstream targets of VEGF in endothelial cells (ECs) are not entirely clarified. Survey of downstream targets of VEGF in human ECs identified a number of genes, including Down syndrome candidate region 1 (DSCR1). This study confirmed the inducible expression of DSCR1 in ECs by Northern and Western blottings. Moreover, VEGF-stimulated induction of DSCR1 is blocked by anti-VEGF receptor-2 monoclonal antibody (mAb), or the specific calcineurin inhibitors cyclosporin A and FK506. The expression of DSCR1 in ECs of neovessels was shown by immunohistochemical analysis. Whether DSCR1 plays any roles in angiogenesis was examined. The specific downregulation of DSCR1 expression by antisense oligonucleotide (AS-ODN) inhibits VEGF-stimulated migration of ECs as well as angiogenesis in vivo. AS-ODN inhibits the spreading of ECs on vitronectin, as well as on the immobilized anti-alphavbeta3 mAb, but not on anti-alphavbeta5 mAb. Moreover, AS-ODN inhibits tyrosine phosphorylation of focal adhesion kinase when ECs are plated on a vitronectin-coated dish. Immunoprecipitation followed by Western blotting showed the coimmunoprecipitation of DSCR1 and integrin alphavbeta3. These results suggest that DSCR1 is involved in angiogenesis by regulating adhesion and migration of ECs via the interaction with integrin alphavbeta3 (Iizuka, 2004).
Down syndrome candidate region 1 (DSCR1) is one of more than 50 genes located in a region of chromosome 21 that has been implicated in Down syndrome. DSCR1 can be expressed as four isoforms, one of which, isoform 4 (DSCR1-4), has recently been found to be strongly induced by vascular endothelial growth factor A [VEGF-A(165)] and to provide a negative feedback loop that inhibits VEGF-A(165)-induced endothelial cell proliferation in vitro and angiogenesis in vivo. Another DSCR1 isoform, DSCR1-1L, is also up-regulated by VEGF-A(165) in cultured endothelial cells and is strongly expressed in several types of pathologic angiogenesis in vivo. In contrast to DSCR1-4, the overexpression of DSCR1-1L induced the proliferation and activation of the transcription factor NFAT in cultured endothelial cells and promoted angiogenesis in Matrigel assays in vivo, even in the absence of VEGF-A. Similarly, small interfering RNAs specific for DSCR1-1L and DSCR1-4 had opposing inhibitory and stimulatory effects, respectively, on these same functions. DSCR1-4 is thought to inhibit angiogenesis by inactivating calcineurin, thereby preventing activation and nuclear translocation of NFAT, a key transcription factor. In contrast, DSCR1-1L, regulated by a different promoter than DSCR1-4, activates NFAT and its proangiogenic activity is inhibited by cyclosporin, an inhibitor of calcineurin. In sum, DSCR1-1L, unlike DSCR1-4, potently activates angiogenesis and could be an attractive target for antiangiogenesis therapy (Qin, 2006).
It was hypothesized that DSCR1 (Adapt78) might also be involved in the development of Alzheimer's disease. To address this question DSCR1 was examined in multiple human tissues and significant expression was found in brain, spinal cord, kidney, liver, mammary gland, skeletal muscle, and heart. Within the brain DSCR1 is predominantly expressed in neurons within the cerebral cortex, hippocampus, substantia nigra, thalamus, and medulla oblongata. When DSCR1 mRNA expression in post-mortem brain samples from Alzheimer's disease patients was compared with expression in individuals who had died with no Alzheimer's diagnosis, it was found that DSCR1 mRNA levels were about twice as high in age-matched Alzheimer's patients as in controls. DSCR1 mRNA levels were actually three times higher in patients with extensive neurofibrillary tangles (a hallmark of Alzheimer's disease) than in controls. In comparison, post-mortem brain samples from Down syndrome patients (who suffer Alzheimer's symptoms) also exhibited DSCR1 mRNA levels two to three times higher than controls. Using a cell culture model it was discovered that the amyloid beta(1-42) peptide, which is a major component of senile plaques in Alzheimer's, can directly induce increased expression of DSCR1. These findings associate DSCR1 with such major hallmarks of Alzheimer's disease as amyloid protein, senile plaques, and neurofibrillary tangles (Ermak, 2001).
The Down syndrome critical region 1 (DSCR1) gene is present in the region of human chromosome 21 and the syntenic region of mouse chromosome 16, trisomy of which is associated with congenital heart defects observed in Down syndrome. DSCR1 encodes a regulatory protein in the calcineurin/NFAT signal transduction pathway. During valvuloseptal development in the heart, DSCR1 is expressed in the endocardium of the developing atrioventricular and semilunar valves, the muscular interventricular septum, and the ventricular myocardium. Human DSCR1 contains an NFAT-rich calcineurin-responsive element adjacent to exon 4. Transgenic mice generated with a homologous regulatory region of the mouse DSCR1 gene linked to lacZ (DSCR1(e4)/lacZ) show gene activation in the endocardium of the developing valves and aorticopulmonary septum of the heart, recapitulating a specific subdomain of endogenous DSCR1 cardiac expression. DSCR1(e4)/lacZ expression in the developing valve endocardium colocalizes with NFATc1 and, endocardial DSCR1(e4)/lacZ, is notably reduced or absent in NFATc1−/− embryos. Furthermore, expression of the endogenous DSCR1(e4) isoform is decreased in the outflow tract of NFATc1−/− hearts, and the DSCR1(e4) intragenic element is trans-activated by NFATc1 in cell culture. In trisomy 16 (Ts16) mice, expression of endogenous DSCR1 and DSCR1(e4)/lacZ colocalizes with anomalous valvuloseptal development, and transgenic Ts16 hearts have increased β-galactosidase activity. DSCR1 and DSCR1(e4)/lacZ also are expressed in other organ systems affected by trisomy 16 in mice or trisomy 21 in humans including the brain, eye, ear, face, and limbs. Together, these results show that DSCR1(e4) expression in the developing valve endocardium is dependent on NFATc1 and support a role for DSCR1 in normal cardiac valvuloseptal formation as well as the abnormal development of several organ systems affected in individuals with Down syndrome (Lange, 2004).
Trisomy 21 results in Down syndrome, but little is known about how a 1.5-fold increase in gene dosage produces the pleiotropic phenotypes of Down syndrome. 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. Mathematical modelling was used 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. Observations of calcineurin-and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down syndrome and human trisomy 21 are consistent with these predictions. It is suggested 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 syndrome. More generally, these observations suggest that the destabilization of regulatory circuits can underlie human disease (Arron, 2006).
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