Curriculum ScienTI
Brazilian Journal of Biology
Print version ISSN 1519-6984On-line version ISSN 1678-4375
Braz. J. Biol. vol.68 no.2 São Carlos May 2008
http://dx.doi.org/10.1590/S1519-69842008000200031
Trisomy 21 and Down syndrome - A short review
Trissomia do 21 e Síndrome de Down: uma breve revisão
Sommer, CA; Henrique-Silva, F.*
Departamento de Genética e Evolução, Universidade Federal de São Carlos – UFSCar, Rodovia Washington Luís, Km 235, CEP 13565-905, São Carlos, SP, Brazil
Even though the molecular mechanisms underlying the Down syndrome (DS) phenotypes remain obscure, the characterization of the genes and conserved non-genic sequences of HSA21 together with large-scale gene expression studies in DS tissues are enhancing our understanding of this complex disorder. Also, mouse models of DS provide invaluable tools to correlate genes or chromosome segments to specific phenotypes. Here we discuss the possible contribution of HSA21 genes to DS and data from global gene expression studies of trisomic samples.
Keywords: Down syndrome, trisomy, HSA21, gene-expression analysis.
Embora os mecanismos moleculares que causam a síndrome de Down (SD) não sejam totalmente conhecidos, a caracterização de genes e seqüências não gênicas conservadas do HSA21 e os estudos de expressão em grande escala em amostras de pacientes com SD estão aumentando o entendimento da síndrome. Por outro lado, os modelos murinos da SD provêm ferramentas valiosas para correlacionar genes ou segmentos cromossômicos a características fenotípicas específicas. Nesta revisão, são discutidas as possíveis contribuições dos genes do HSA21 à SD e os dados de estudos de expressão gênica global de amostras trissômicas.
Palavras-chave: Síndrome de Down, trissomia do 21, HSA21, análise da expressão gênica.
Trisomy 21 is the most common genetic cause of mental retardation and one of the few aneuploidies compatible with post-natal survival. It occurs in 1 out of 700 live births in all ethnic groups (Epstein, 2001). The vast majority of meiotic errors leading to the trisomic condition occur in the egg, as nearly 90% of cases involve an additional maternal chromosome (Hassold and Sherman, 2000). Besides mental retardation, present in every individual with Down syndrome (DS), trisomy 21 is associated with more than 80 clinical traits including congenital heart disease, duodenal stenosis or atresia, imperforate anus, Hirschprung disease, muscle hypotonia, immune system deficiencies, increased risk of childhood leukemia and early onset Alzheimer's disease (Epstein et al., 1991). The severity of each of the phenotypic features is highly variable among the patients. In this sense, the identification of single nucleotide polymorphisms (SNPs) on HSA21 provides a tool to study the contribution of the allelic variability to the phenotypic variability (Deutsch et al., 2001).
It is widely assumed that the DS complex phenotype results from the dosage imbalance of the genes located on HSA21. The products of these genes act directly or indirectly, by affecting the expression of disomic genes. This hypothetical model requires different experimental approaches that include, but are not restricted to, the complete characterization of HSA21 genes and non-coding sequences and the analysis of the global gene expression changes induced by trisomy in every tissue/cell type available and at different developmental stages.
2. Human Chromosome 21
The genetic nature of DS together with the relatively small size of HSA21 encouraged scientists to concentrate efforts towards the complete characterization of this chromosome in the past few years. The almost complete DNA sequence of the long arm (21q) of HSA21 was determined and published in Nature (Hattori et al., 2000). This represented a breakthrough for research in DS, greatly assisting in the identification of every gene and non-coding sequence of 21q.
The length of 21q is 33.5 Mb and approximately 3% of its sequence encodes for proteins. The initial analysis of 21q revealed 225 genes (127 known genes and 98 putative novel genes predicted in silico) and 59 pseudogenes (Hattori et al., 2000). Although the precise gene catalogue has not yet been conclusively determined, Gardiner et al. (2003) have estimated 364 genes and putative genes from the finished sequence of HSA21. The proteins encoded by these genes fall into several functional categories including transcription factors, regulators and modulators (18 genes); proteases and protease inhibitors (6 genes); ubiquitin pathway (4 genes); interferons and immune response (9 genes); kinases (8 genes); RNA processing (5 genes); adhesion molecules (4 genes); channels (7 genes); receptors (5 genes); and energy metabolism (4 genes). Interestingly, ~1% of the HSA21 corresponds to conserved non-genic (CNG) sequences, that is, sequences that are not "functionally" transcribed and do not correspond to protein-coding genes (Dermitzakis et al., 2002; Dermitzakis et al., 2004). The significant conservation of these sequences indicates that they are functional, although their function is unknown.
The identification and characterization of HSA21 genes may improve our understanding of the molecular basis of the disease. Even before the complete sequence of 21q was determined, an intensive work started towards the characterization of HSA21 genes. The existence of a "Down Syndrome Critical Region" (DSCR), a small segment of HSA21 that contains genes responsible for many features of DS, has dominated the field of DS research for three decades. Accordingly, a number of genes contained in this ~5.4 Mb region have been extensively studied as an attempt to find out their potential contributions to DS. Two of these genes are DSCR1 and DSCR2.
The DSCR1 ("Down Syndrome Critical Region 1") protein, now renamed RCAN1 (from "Regulator of Calcineurin 1") (Davies et al., 2007) is over-expressed 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 (Fuentes et al., 2000; Harris et al., 2005). RCAN1 is highly expressed in the human brain and heart suggesting that its overexpression may be involved in the pathogenesis of Down syndrome, particularly mental retardation and/or cardiac defects (Fuentes et al., 1995). Previous studies identified conserved residues involved in the subcellular location of RCAN1 (Pfister et al., 2002) and provided evidence that it may play a functional role in the nucleus, probably as a regulator of transcription (Silveira et al., 2004). Recently, Arron et al. (2006) reported that the genes RCAN1 and DYRK1A, both contained within the DSCR, act synergistically to prevent the nuclear occupancy of NFATc transcription factors. They suggested that the 1.5-fold increase in dosage of RCAN1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome.
The gene DSCR2 ("Down Syndrome Critical Region 2") is highly expressed in all proliferating tissues and cells, such as fetal tissues, adult testis and cancer cell lines (Vidal-Taboada et al., 2000). The intracellular localization and proteolytic cleavage of the protein have been carefully studied (Abrão-Possik et al., 2004; Vesa et al., 2005). Hirano et al. (2005) have recently designated DSCR2 as "Proteasome Assembling Chaperone-1" (PAC1). PAC1 and PAC2 are chaperones that function as heterodimers in the maturation of mammalian 20S proteasomes. Overexpression of PAC1 or PAC2 accelerates the formation of precursor proteasomes, whereas knockdown by short interfering RNA impairs it, resulting in poor maturation of 20S proteasomes (Hirano et al., 2005). Thus, the product of the gene DSCR2 is involved in the correct assembly of 20S proteasomes.
Of note, there are eighteen genes located on HSA21 that encode transcription factors and co-regulators/modulators of transcription. These proteins are directly and indirectly involved in transcription regulation and alterations in their expression levels could impact the expression of downstream targets. This notion is supported by a number of studies reporting the dysregulation of disomic genes in DS tissues (see references below). The identification of the targets of these regulators is of prime importance to assess their contribution to the molecular pathogenesis of DS.
Despite the great efforts made in the search for a "critical region", the existence of individual loci on HSA21 responsible for producing the clinical features of DS has not been demonstrated (Shapiro, 1999). Indeed, a recent study provided the evidence that trisomy for the DSCR is necessary but not sufficient for the brain phenotypes observed in trisomic mice (Olson et al., 2007). Thus, although HSA21 genes are likely to contribute to DS, the abnormalities seen in the patients are multifactorial conditions (Shapiro, 1999) and are the result of genetic, environmental and stochastic influences (Reeves et al., 2001). Besides the complete characterization of HSA21 genes, we need to understand the transcriptional effects caused by trisomy 21.
3. Transcriptional Consequences of Trisomy 21
A model for the transcriptional consequences of trisomy has been proposed recently (FitzPatrick, 2005). An extra copy of HSA21 genes would result in a 1.5-fold increase in the expression of many of them, some of which will produce a phenotypic effect directly. Overexpression of HSA21 genes that encode trans-acting factors is expected to induce a mis-regulation of disomic genes. The primary gene-dosage effects as well as the trans-acting gene-dosage effects will produce a phenotypic effect, which will result in a tertiary apparent "mis-regulation" of disomic genes. The presence of CNG sequences on HSA21 indicates that they may also have a role in the generation of DS phenotypes although this has yet to be confirmed. Some of the genes for which evidence indicates over-expression in DS brain are listed in Table 1.
Several studies have reported a generalized overexpression of triplicated genes at the mRNA level in mouse models of DS (Amano et al., 2004; Lyle et al., 2004; Kahlem et al., 2004; Dauphinot et al., 2005). Interestingly, studies performed on human trisomic tissues indicate that only a subset of HSA21 genes is over-expressed relative to euploid controls and that the increase in expression may be different from the expected ~1.5-fold (FitzPatrick et al., 2002; Tang et al., 2004; Mao et al., 2005). Also, the set of over-expressed HSA21 genes differs across the trisomic cell types (Li et al., 2006). These findings indicate that the presence of three copies of a gene does not necessarily result in overexpression and that other factors (e.g. developmental stage, tissue-specific differences) also affect gene expression.
The extensive variation in the expression of HSA21 genes observed among unaffected individuals (Deutsch et al., 2005) might underlie some of the phenotypic variability seen in the patients. The determination of which genes are significantly over-expressed in DS is largely dependent on the degree of gene-expression variation: while some HSA21 genes show little or no overlap in the distribution of expression values between DS and control samples, others show overlapping distributions with varying degrees (Prandini et al., 2007). Furthermore, a recent report indicates that many HSA21 genes are likely to be compensated in DS and some of them are highly variable among individuals (Aït Yahya-Graison et al., 2007). The genes with minimal expression overlap are over-expressed in DS and probably associated with the constant DS features; those with partially overlapping expression distributions could account for the variable features. Assessment of this natural gene-expression variation in several DS tissues will provide information to identify candidate genes. In addition, the characterization of the protein profiles of trisomic samples will be of importance to see how well the transcript levels correlate with the corresponding protein products.
The increase in expression of some HSA21 genes would induce changes in the global gene expression pattern that ultimately contribute to the DS phenotypic features. A number of studies have reported dysregulation of disomic genes in DS tissues (FitzPatrick et al., 2002; Tang et al., 2004; Mao et al., 2005). Different sets of non-HSA21 genes show up- or down regulation as a consequence of chromosomal imbalance. It is likely that some (if not all) the DS phenotypic features are not directly attributable to single gene(s) but are at least in part the result of a more generalized gene dysregulation caused by the triplicated chromosome. A recent study in fetal hearts of trisomic subjects provided additional evidence supporting the existence of a dysregulation of non-HSA21 genes associated with the primary gene-dosage effect. Interestingly, functional clustering of dysregulated genes revealed down-regulation of genes encoding mitochondrial enzymes and up-regulation of genes encoding extracellular matrix proteins in DS, suggesting an association of these alterations with the heart defects (Conti et al., 2007). As each tissue is characterized by a distinct proteome, we expect that different sets of disomic genes will be subject to dysregulation in the various tissues. Therefore, every tissue/cell type available should be investigated.
We have analyzed the gene expression profile of DS lymphocytes using SAGE "Serial Analysis of Gene Expression". SAGE is a powerful technique that allows the characterization of global gene expression profiles (Velculescu et al., 1995). In the SAGE method, 10-base tags are obtained from each transcript, concatenated, and sequenced. By cataloging tags along with their frequencies and identifying corresponding genes, we can estimate the expression level of thousands of genes simultaneously. Among the significantly differentially expressed SAGE tags, many corresponded to genes involved in transcription, RNA processing, signaling, immune response and lipid metabolism. Our results suggest that trisomy 21 induces a modest dysregulation of disomic genes that may be related to the immunological perturbations seen in DS (Sommer et al., 2008). In a previous study, we used SAGE to generate a comprehensive expression profile of DS leukocytes (Malago-Junior et al., 2005). The availability of the SAGE data may aid in the identification of gene signatures associated with specific treatments and therapeutic interventions of DS blood cells.
4. Mouse Models of DS
The studies performed on human trisomic tissues are restricted because of practical and ethical reasons. In contrast, mouse models of human disorders provide access to all tissues at all stages of development. Regardless of the species-specific differences between human and mouse, they have become indispensable tools for dissecting the phenotypic consequences of imbalances that affect single genes or chromosome segments. Although the current murine models of DS do not show all the features of the syndrome, they have greatly enhanced our understanding of the cellular and biochemical mechanisms involved.
Mouse orthologues of chromosome 21 genes are located on three chromosomes: MMU16 (~23 Mb), MMU17 (~1.1 Mb), and MMU10 (~2.3 Mb). The most widely used models are the segmental trisomy strains Ts65Dn and Ts1Cje that contain several HSA21 orthologs in three copies. Both display overlapping phenotypes that parallel those seen in DS, including learning and behavioral deficits (Reeves et al., 1995; Sago et al., 1998). Two additional mouse models have been developed recently. O'Doherty et al. (2005) created the "transchromosomic" mouse Tc1, which carries an almost complete copy of HSA21 and have heart defects like those seen in DS patients, together with spatial learning and memory deficits. The segmental trisomy mouse model Ts1Rh is trisomic for the DSCR (Olson et al., 2004). Other mouse models trisomic for smaller HSA21 syntenic regions or even single genes should be generated to assess their putative contribution to the DS specific abnormalities.
5. Conclusions and Perspectives
The molecular mechanisms leading to DS are incompletely understood. The inconsistencies found in large scale transcriptome studies of trisomic tissues along with the extensive gene-expression variation of HSA21 genes indicate that more research is needed before we can elucidate the numerous pathogenic mechanisms associated with this complex disorder. In this sense, mouse models of DS provide invaluable tools to correlate genes or chromosome segments to specific phenotypes. It will be some time before we can start considering the development of strategies for prevention and treatment of some DS related pathologies.
AÏT YAHYA-GRAISON, E., AUBERT, J., DAUPHINOT, L., RIVALS, I., PRIEUR, M., GOLFIER, G., ROSSIER, J., PERSONNAZ, L., CRÉAU, N., BLÉHAUT, H., ROBIN, S., DELABAR, JM. and POTIER, MC., 2007. Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. Am. J. Hum. Genet., vol. 81, no. 3, p. 475-491. [ Links ]
AMANO, K., SAGO, H., UCHIKAWA, C., SUZUKI, T., KOTLIAROVA, SE., NUKINA, N., EPSTEIN, CJ. and YAMAKAWA, K., 2004. Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome. Hum. Mol. Genet., vol. 13, no. 13, p. 1333-1340. [ Links ]
ARAI, Y., IJUIN, T., TAKENAWA, T., BECKER, LE. and TAKASHIMA, S., 2002. Excessive expression of synaptojanin in brains with Down syndrome. Brain Dev., vol. 24, no. 2, p. 67-72. [ Links ]
ARRON, JR., WINSLOW, MM., POLLERI, A., CHANG, CP., WU, H., GAO, X., NEILSON, JR., CHEN, L., HEIT, JJ., KIM, SK., YAMASAKI, N., MIYAKAWA, T., FRANCKE, U., GRAEF, IA. and CRABTREE, GR., 2006. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature, vol. 441, no. 7093, p. 595-600. [ Links ]
BARBIERO, L., BENUSSI, L., GHIDONI, R., ALBERICI, A., RUSSO, C., SCHETTINI, G., PAGANO, SF., PARATI, EA., MAZZOLI, F., NICOSIA, F., SIGNORINI, S., FEUDATARI, E. and BINETTI, G., 2003. BACE-2 is overexpressed in Down's syndrome. Exp. Neurol., vol. 182, no. 2, p. 335-345. [ Links ]
CONTI, A., FABBRINI, F., D'AGOSTINO, P., NEGRI, R., GRECO, D., GENESIO, R., D'ARMIENTO, M., OLLA, C., PALADINI, D., ZANNINI, M. and NITSCH, L., 2007. Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy. BMC Genomics, vol. 8, p. 268. [ Links ]
DAUPHINOT, L., LYLE, R., RIVALS, I., DANG MT., MOLDRICH, RX., GOLFIER, G., ETTWILLER, L., TOYAMA, K., ROSSIER, J., PERSONNAZ, L., ANTONARAKIS, SE., EPSTEIN, CJ., SINET, P-M. and POTIER, M-C., 2005. The cerebellar transcriptome during postnatal development of the Ts1Cje mouse, a segmental trisomy model for Down syndrome. Hum. Mol. Genet., vol. 14, no. 3, p. 373-384. [ Links ]
DAVIES, KJ., ERMAK, G., ROTHERMEL, BA., PRITCHARD, M., HEITMAN, J., AHNN, J., HENRIQUE-SILVA, F., CRAWFORD, D., CANAIDER, S., STRIPPOLI, P., CARINCI, P., MIN, KT., FOX, DS., CUNNINGHAM, KW., BASSEL-DUBY, R., OLSON, EN., ZHANG, Z., WILLIAMS, RS., GERBER, HP., PÉREZ-RIBA, M., SEO, H., CAO, X., KLEE, CB., REDONDO, JM., MALTAIS, LJ., BRUFORD, EA., POVEY, S., MOLKENTIN, JD., MCKEON, FD., DUH, EJ., CRABTREE, GR., CYERT, MS., DE LA LUNA, S. and ESTIVILL, X., 2007. Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. FASEB J., vol. 21, no. 12, p. 3023-3028. [ Links ]
DERMITZAKIS, ET., KIRKNESS, E., SCHWARZ, S., BIRNEY, E., REYMOND, A. and ANTONARAKIS, SE., 2004. Comparison of human chromosome 21 conserved nongenic sequences (CNGs) with the mouse and dog genomes shows that their selective constraint is independent of their genic environment. Genome Res., vol. 14, no. 5, p. 852-859. [ Links ]
DERMITZAKIS, ET., REYMOND, A., LYLE, R., SCAMUFFA, N., UCLA, C., DEUTSCH, S., STEVENSON, BJ., FLEGEL, V., BUCHER, P., JONGENEEL, CV. and ANTONARAKIS, SE., 2002. Numerous potentially functional but non-genic conserved sequences on human chromosome 21. Nature, vol. 420, no. 6915, p. 578-582. [ Links ]
DEUTSCH, S., ISELI, C., BUCHER, P., ANTONARAKIS, SE. and SCOTT, HS., 2001. A cSNP map and database for human chromosome 21. Genome Res., vol. 11, no. 2, p. 300-307. [ Links ]
DEUTSCH, S., LYLE, R., DERMITZAKIS, ET., ATTAR, H., SUBRAHMANYAN, L., GEHRIG, C., PARAND, L., GAGNEBIN, M., ROUGEMONT, J., JONGENEEL, CV. and ANTONARAKIS, SE., 2005. Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes. Hum. Mol. Genet., vol. 14, no. 23, p. 3741-3749. [ Links ]
DOWJAT, WK., ADAYEV, T., KUCHNA, I., NOWICKI, K., PALMINIELLO, S., HWANG, YW. and WEGIEL, J., 2007. Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome. Neurosci. Lett., vol. 413, no. 1, p. 77-81. [ Links ]
EPSTEIN, CJ., 2001. Down Syndrome (trisomy 21), In SCRIVER, CR., BEAUDET, AL., SLY, WS. and VALLE, D. (eds.), The metabolic and molecular bases of inherited diseases. McGraw-Hill, Inc., NewYork, p. 1223-1256. [ Links ]
EPSTEIN, CJ., KORENBERG, JR., ANNEREN, G., ANTONARAKIS, SE., AYME, S., COURCHESNE, E., EPSTEIN, LB., FOWLER, A., GRONER, Y., HURET, JL., KEMPER, TL., LOTT, IT., LUBIN, BH., MAGENIS, E., OPITZ, JM., PATTERSON, D., PRIEST, JH., PUESCHEL, SM., RAPOPORT, SI., SINET, PM., TANZI, RE. and DE LA CRUZ, F., 1991. Protocols to establish genotype-phenotype correlations in Down syndrome. Am. J. Hum. Genet., vol. 49, no. 1, p. 207-235. [ Links ]
FERRANDO-MIGUEL, R., CHEON, MS., YANG, JW. and LUBEC, G., 2003a. Overexpression of transcription factor BACH1 in fetal Down syndrome brain. J. Neural. Transm. Suppl., vol. 67, p. 193-205. [ Links ]
FERRANDO-MIGUEL, R., SHIM, K., CHEON, MS., GIMONA, M., FURUSE, M. and LUBEC, G., 2003b. Overexpression of interferon α/β receptor β chain in fetal Down syndrome brain. Neuroembryology, vol. 2, p. 147-155. [ Links ]
FITZPATRICK, DR., 2005. Transcriptional consequences of autosomal trisomy: primary gene dosage with complex downstream effects. Trends Genet., vol. 21, no. 5, p. 249-253. [ Links ]
FITZPATRICK, DR., RAMSAY, J., McGILL, NI., SHADE, M., CAROTHERS, AD. and HASTIE, ND., 2002. Transcriptome analysis of human autosomal trisomy. Hum. Mol. Genet., vol. 11, no. 26, p. 3249-3256. [ Links ]
FUENTES, JJ., GENESCA, L., KINGSBURY, TJ., CUNNINGHAM, KW., PEREZ-RIBA, M., ESTIVILL, X. and DE LA LUNA, S., 2000. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum. Mol. Genet., vol. 9, no. 11, p. 1681-1690. [ Links ]
FUENTES, JJ., PRITCHARD, MA., PLANAS, AM., BOSCH, A., FERRER, I. and ESTIVILL, X., 1995. A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum. Mol. Genet., vol. 4, no. 10, p. 1935-1944. [ Links ]
GARDINER, K. and DAVISSON, M., 2000. The sequence of human chromosome 21 and implications for research into Down syndrome. Genome Biol., vol. 1, no. 2, reviews 0002.1-0002.9. [ Links ]
GARDINER, K., FORTNA, A., BECHTEL, L. and DAVISSON, MT., 2003. Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions. Gene, vol. 318, p. 137-147. [ Links ]
GULESSERIAN, T., SEIDL, R., HARDMEIER, R., CAIRNS, R. and LUBEC, G., 2001. Superoxide dismutase SOD1, encoded on chromosome 21, but not SOD2 is overexpressed in brains of patients with Down syndrome. J. Invest. Med., vol. 49, no. 1, p. 41-46. [ Links ]
HARRIS, CD., ERMAK, G. and DAVIES, KJ., 2005. Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product Calcipressin 1 (or RCAN1) in disease. Cell. Mol. Life Sci., vol. 62, no. 21, p. 2477-2486. [ Links ]
HASSOLD, T. and SHERMAN, S., 2000. Down syndrome: genetic recombination and the origin of the extra chromosome 21. Clin. Genet., vol. 57, no. 2, p. 95-100. [ Links ]
HATTORI, M., FUJIYAMA, A., TAYLOR, TD., WATANABE, H., YADA, T., PARK, HS., TOYODA, A., ISHII, K., TOTOKI, Y., CHOI, DK., GRONER, Y., SOEDA, E., OHKI, M., TAKAGI, T., SAKAKI, Y., TAUDIEN, S., BLECHSCHMIDT, K., POLLEY, A., MENZEL, U., DELABAR, J., KUMPF, K., LEHMANN, R., PATTERSON, D., REICHWALD, K., RUMP, A., SCHILLHABEL, M., SCHUDY, A., ZIMMERMANN, W., ROSENTHAL, A., KUDOH, J., SCHIBUYA, K., KAWASAKI, K., ASAKAWA, S., SHINTANI, A., SASAKI, T., NAGAMINE, K., MITSUYAMA, S., ANTONARAKIS, SE., MINOSHIMA, S., SHIMIZU, N., NORDSIEK, G., HORNISCHER, K., BRANT, P., SCHARFE, M., SCHON, O., DESARIO, A., REICHELT, J., KAUER, G., BLOCKER, H., RAMSER, J., BECK, A., KLAGES, S., HENNIG, S., RIESSELMANN, L., DAGAND, E., HAAF, T., WEHRMEYER, S., BORZYM, K., GARDINER, K., NIZETIC, D., FRANCIS, F., LEHRACH, H., REINHARDT, R. and YASPO, ML., 2000. The DNA sequence of human chromosome 21. Nature, vol. 405, no. 6784, p. 311-319. [ Links ]
HIRANO, Y., HENDIL, KB., YASHIRODA, H., IEMURA, S., NAGANE, R., HIOKI, Y., NATSUME, T., TANAKA, K. and MURATA, S., 2005. A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes. Nature, vol. 437, no. 7063, p. 1381-1385. [ Links ]
KAHLEM, P., SULTAN, M., HERWIG, R., STEINFATH, M., BALZEREIT, D., EPPENS, B., SARAN, NG., PLETCHER, MT., SOUTH, ST., STETTEN, G., LEHRACH, H., REEVES, RH. and YASPO, ML., 2004. Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of Down syndrome. Genome Res., vol. 14, no. 7, p. 1258-1267. [ Links ]
LI, CM., GUO, M., SALAS, M., SCHUPF, N., SILVERMAN, W., ZIGMAN, WB., HUSAIN, S., WARBURTON, D., THAKER, H. and TYCKO, B., 2006. Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21. BMC Med. Genet., vol. 7, p. 24. [ Links ]
LYLE, R., GEHRIG, C., NEERGAARD-HENRICHSEN, C., DEUTSCH, S. and ANTONARAKIS, SE., 2004. Gene expression from the aneuploid chromosome in a trisomy mouse model of Down syndrome. Genome Res., vol. 14, no. 7, p. 1268-1274. [ Links ]
MALAGO-JUNIOR, W., SOMMER, CA., DEL CISTIA ANDRADE, C., SOARES-COSTA, A., POSSIK, PA., CASSAGO, A., SILVEIRA, HCS. and HENRIQUE-SILVA, F., 2005. Gene expression profile of human Down syndrome leukocytes. Croat. Med. J., vol. 46, no. 4, p. 647-656. [ Links ]
MAO, R., WANG, X., SPITZNAGEL-JUNIOR, EL., FRELIN, LP., TING, JC., DING, H., KIM, JW., RUCZINSKI, I., DOWNEY, TJ. and PEVSNER, J., 2005. Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart. Genome Biol., vol. 6, no. 13, p. R107. [ Links ]
O'DOHERTY, A., RUF, S., MULLIGAN, C., HILDRETH, V., ERRINGTON, ML., COOKE, S., SESAY, A., MODINO, S., VANES, L., HERNANDEZ, D., LINEHAN, JM., SHARPE, PT., BRANDNER, S., BLISS, TB., HENDERSON, DJ., NIZETIC, D., TYBULEWICZ, VLJ. and FISHER, EM., 2005. An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science, vol. 309, no. 5743, p. 2033-2037. [ Links ]
OLSON, LE., RICHTSMEIER, JT., LESZL, J. and REEVES, RH., 2004. A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science, vol. 306, no. 5696, p. 687-690. [ Links ]
OLSON, LE., ROPER, RJ., SENGSTAKEN, CL., PETERSON, EA., AQUINO, V., GALDZICKI, Z., SIAREY, R., PLETNIKOV, M., MORAN, TH. and REEVES, RH., 2007. Trisomy for the Down syndrome "critical region" is necessary but not sufficient for brain phenotypes of trisomic mice. Hum. Mol. Genet., vol. 16, no. 7, p. 774-782. [ Links ]
PFISTER, SC., MACHADO-SANTELLI, GM., HAN, SW. and HENRIQUE-SILVA, F., 2002. Mutational analyses of the signals involved in the subcellular location of DSCR1. BMC Cell Biol., vol. 3, p. 24. [ Links ]
POSSIK, PA., SOMMER, CA., ISSA HORI, J., MACHADO-SANTELLI, GM., JAMUR, MC. and HENRIQUE-SILVA, F., 2004. DSCR2, a Down syndrome critical region protein, is localized to the endoplasmic reticulum of mammalian cells. Eur. J. Histochem., vol. 48, no. 3, p. 267-272. [ Links ]
PRANDINI, P., DEUTSCH, S., LYLE, R., GAGNEBIN, M., VIVIER, CD., DELORENZI, M., GEHRIG, C., DESCOMBES, P., SHERMAN, S., BRICARELLI, FD., BALDO, C., NOVELLI, A., DALLAPICCOLA, B. and ANTONARAKIS, SE., 2007. Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. Am. J. Hum. Genet., vol. 81, no. 2, p. 252-263. [ Links ]
REEVES, RH., BAXTER, LL. and RICHTSMEIER, JT., 2001. Too much of a good thing: mechanisms of gene action in Down syndrome. Trends Genet., vol. 17, no. 2, p. 83-88. [ Links ]
REEVES, RH., IRVING, NG., MORAN, TH., WOHN, A., KITT, C., SISODIA, SS., SCHMIDT, C., BRONSON, RT. and DAVISSON, MT., 1995. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nature Genet., vol. 11, no. 2, p. 177-184. [ Links ]
SAGO, H., CARLSON, EJ., SMITH, DJ., KILBRIDGE, J., RUBIN, EM., MOBLEY, WC., EPSTEIN, CJ. and HUANG, TT., 1998. Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc. Natl. Acad. Sci. U.S.A., vol. 95, no. 11, p. 6256-6261. [ Links ]
SAITO, Y., OKA, A., MIZGUCHI, M., MOTONAGA, K., MORI, Y., BECKER, LE., ARIMA, K., MIYAUCHI, J. and TAKASHIMA, S., 2000. The developmental and aging changes of Down syndrome cell adhesion molecule expression in normal and Down syndrome brains. Acta Neuropathol., vol. 100, no. 6, p. 654-664. [ Links ]
SANCHEZ-FONT, MF., BOSCH-COMAS, A., GONZALEZ-DUARTE, R. and MARFANY, G., 2003. OVEREXPRESSION of FABP7 in Down syndrome fetal brains is associated with PKNOX1 gene-dosage imbalance. Nucleic Acids Res., vol. 31, no. 11, p. 2769-2777. [ Links ]
SHAPIRO, BL., 1999. The Down syndrome critical region. J. Neural. Transm. Suppl., vol. 57, p. 41-60. [ Links ]
SHIM, KS., FERRANDO-MIGUEL R. and LUBEC, G., 2003. Aberrant protein expression of transcription factors BACH1 and ERG, both encoded on chromosome 21, in brains of patients with Down syndrome and Alzheimer's disease. J. Neural. Transm. Suppl., vol. 67, p. 39-49. [ Links ]
SILVEIRA, HCS., SOMMER, CA., SOARES-COSTA, A. and HENRIQUE-SILVA, F., 2004. A calcineurin inhibitory protein overexpressed in Down's Syndrome interacts with the product of a ubiquitously expressed transcript. Brazil. J. Med. Biol. Res., vol. 37, no. 6, p. 785-789. [ Links ]
SOMMER, CA., PAVARINO-BERTELLI, EC., GOLONI-BERTOLLO, EM. and HENRIQUE-SILVA, F., 2008. Identification of dysregulated genes in lymphocytes from children with Down syndrome. Genome, vol. 51, no. 1, p. 19-29. [ Links ]
TANG, Y., SCHAPIRO, MB., FRANZ, DN., PATTERSON, BJ., HICKEY, FJ., SCHORRY, EK., HOPKIN, RJ., WYLIE, M., NARAYAN, T., GLAUSER, TA., GILBERT, DL., HERSHEY, AD. and SHARP, FR., 2004. Blood expression profiles for tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome. Ann. Neurol., vol. 56, no. 6, p. 808-814. [ Links ]
VELCULESCU, VE., ZHANG, L., VOGELSTEIN, B. and KINZLER, KW., 1995. Serial analysis of gene expression. Science, vol. 270, no. 5235, p. 484-487. [ Links ]
VESA, J., BROWN, Y., GREENFIELD, D. and KORENBERG, JR., 2005. Molecular and cellular characterization of the Down syndrome critical region protein 2. Biochem. Biophys. Res. Commun., vol. 328, no. 1, p. 235-242. [ Links ]
VIDAL-TABOADA, JM., LU, A., PIQUE, M., PONS, G., GIL, J. and OLIVA, R., 2000. Down Syndrome Critical Region Gene 2: Expression during mouse development and in human cell lines indicates a function related to cell proliferation. Biochem. Biophys. Res. Commun., vol. 272, no. 1, p. 156-163. [ Links ]
WOLVETANG, EJ., WILSON, TJ., SANIJ, E., BUSCIGLIO, J., HATZISTAVROU, T., SETH, A., HERTZOG, PJ. and KOLA, I., 2003. ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway. Hum. Mol. Genet., vol. 12, no. 3, p. 247-255. [ Links ]
Received June 29, 2007
Accepted August 20, 2007
Distributed May 31, 2008
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