Trisomy Disorders

Posts Tagged ‘trisomy 21

Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome.

Feb 2012


Individuals with Down syndrome (DS; also known as trisomy 21) have a markedly increased risk of leukemia in childhood but a decreased risk of solid tumors in adulthood. Acquired mutations in the transcription factor-encoding GATA1 gene are observed in nearly all individuals with DS who are born with transient myeloproliferative disorder (TMD), a clonal preleukemia, and/or who develop acute megakaryoblastic leukemia (AMKL). Individuals who do not have DS but bear germline GATA1 mutations analogous to those detected in individuals with TMD and DS-AMKL are not predisposed to leukemia. To better understand the functional contribution of trisomy 21 to leukemogenesis, we used mouse and human cell models of DS to reproduce the multistep pathogenesis of DS-AMKL and to identify chromosome 21 genes that promote megakaryoblastic leukemia in children with DS. Our results revealed that trisomy for only 33 orthologs of human chromosome 21 (Hsa21) genes was sufficient to cooperate with GATA1 mutations to initiate megakaryoblastic leukemia in vivo. Furthermore, through a functional screening of the trisomic genes, we demonstrated that DYRK1A, which encodes dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A, was a potent megakaryoblastic tumor-promoting gene that contributed to leukemogenesis through dysregulation of nuclear factor of activated T cells (NFAT) activation. Given that calcineurin/NFAT pathway inhibition has been implicated in the decreased tumor incidence in adults with DS, our results show that the same pathway can be both proleukemic in children and antitumorigenic in adults.

Journal of Clinical Investigation

Herron: Down syndrome an oft misunderstood disorder
By Mason Herron / Columnist
published: Tue, 15 Sep, 2009

When we reflect upon the progress humanity has made, we often reach two conclusions: praise for the progress and the heroes that brought it and the realization of how much more progress must be made. Historically speaking, there are a plethora of examples to this law: colonialism, religious tolerance, civil rights, gender equality, etc.

You get the idea. Perhaps, then, we might consider these reflections and apply them to an issue of today that might not be as eminent but is nonetheless in dire need of grave reflection and consideration, and that is the way we perceive the nature of Down syndrome.

Down syndrome — also referred to as trisomy 21 — is a disorder brought on by the presence of an additional chromosome in an individual’s genes. People who have the disorder are typically developmentally disabled and display below-average cognitive ability. Physical characteristics include low muscle tone, almond-shaped eyes, a flat nasal bridge, a protruding tongue and a number of other features. Each individual might experience these characteristics with different intensities and variability.Down syndrome occurs in one of every 800 births, and the risk of conceiving a child with Down syndrome increases as women grow older, with women older than 35 having 80 percent of Down syndrome births.
 Our understanding of Down syndrome — and the way it was portrayed — was, until recently, simple at best and cruel at worst. The disorder was popularly referred to as “mongolism” (in reference to a Mongoloid race), and the term still creeps its way into modern medical texts. Worse, however, was the implementation of a policy in the early 20th century by 33 of 48 states that mandated that individuals with Down syndrome be forced to undergo involuntary sterilization, and many were murdered by Nazi Germany’s “Action T4” euthanasia program.

This history reveals not only a lack of ethics in regard to the mentally disabled, but also a severe underestimation of the capabilities of those who are born with Down syndrome. A generation after many of those with Down syndrome would have been institutionalized, many are able to happily live and work independently. Many are also perfectly literate, and I hope I need not point out the remarkable athletic talent and leadership displayed at Special Olympics events across the country.

But then one reads this: “It is crucial to reaffirm the morality of aborting a fetus diagnosed with Down syndrome … Because a person afflicted with Down syndrome is only capable of being marginally productive (if at all),” Nicholas Provenzo, founder of the Center for the Advancement of Capitalism, said.

Perhaps no one has said it better than online blogger, Diana Hsieh. “[Christians] would regard abortion as a moral way to prevent the infliction of a miserable, degraded life on the person that will emerge from the womb. Instead, they want to create more mentally defective and perpetually dependent children by outlawing abortion.”

A 2002 study revealed that 91 to 93 percent of Down syndrome pregnancies were intentionally terminated. Many potential parents are unwilling to take on the burdens and uncertainties of raising a disabled child. However, these fears are often exacerbated by a misunderstanding of Down syndrome. According to a congressional testimony by Dr. Brian Skotko, mothers included in his study that had been diagnosed as having a Down syndrome pregnancy “reported that doctors did not tell them about the positive potential of people with Down syndrome, nor did they feel like they received enough up-to-date information or contact information for parent support groups.”

Efforts have been made to rectify this concern. The bi-partisan Prenatally and Postnatally Diagnosed Conditions Awareness Act, signed by President Bush in October 2008, is a bill that seeks to inform and educate the public about Down syndrome and other prenatally or postnatally diagnosed disorders. Fortunately, government has not been the only instrument used toward the proliferation of information regarding Down syndrome. Many organizations, including the National Association for Down Syndrome, the National Down Syndrome Society and the Down Syndrome Association of Pittsburgh, have done work to educate others about this condition, as well.

It seems our immediate impressions of people often get the best of us. In the eyes of some, those with Down syndrome live an incomplete life, an unfair life. Yet we must realize this is not always the case and that those with Down syndrome shouldn’t be defined by their disorder. By willfully changing our perceptions on this particular issue, we take a step toward contributing to the progress of humanity as a whole.

E-mail Mason at


Congenital gastrointestinal defects in Down syndrome: a report from the Atlanta and National Down Syndrome Projects.

Clin Genet. 2008 Nov 17

Freeman SB, Torfs CP, Romitti PA, Royle MH, Druschel C, Hobbs CA, Sherman SL.
Department of Human Genetics, Emory University, Atlanta, GA, USA.

We report Down syndrome (DS)-associated congenital gastrointestinal (GI) defects identified during a 15 year, population-based study of the etiology and phenotypic consequences of trisomy 21. Between 1989 and 2004, six sites collected DNA, clinical and epidemiological information on live-born infants with standard trisomy 21 and their parents. We used chi-squared test and logistic regression to explore relationships between congenital GI defects and infant sex, race, maternal age, origin of the extra chromosome 21, and presence of a congenital heart defect. Congenital GI defects were present in 6.7% of 1892 eligible infants in this large, ethnically diverse, population-based study of DS. Defects included esophageal atresia/tracheoesophageal fistula (0.4%), pyloric stenosis (0.3%), duodenal stenosis/atresia (3.9%), Hirschsprung disease (0.8%), and anal stenosis/atresia (1.0%). We found no statistically significant associations between these defects and the factors examined. Although not significant, esophageal atresia was observed more often in infants of younger mothers and Hispanics, Hirschsprung disease was more frequent in males and in infants of younger mothers and blacks, and anal stenosis/atresia was found more often among females and Asians.


Congenital heart disease in children with Down’s syndrome: Turkish experience of 13 years.

Acta Cardiol. 2008 Oct

Nisli K, Oner N, Candan S, Kayserili H, Tansel T, Tireli E, Karaman B, Omeroglu RE, Dindar A, Aydogan U, Başaran S, Ertugrul T.
Paediatric Cardiology Division, Paediatrics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.

BACKGROUND: Down’s syndrome (DS) is the most common chromosomal abnormality due to a trisomy of chromosome 21 commonly associated with congenital heart defects (CHDs). This study aimed to evaluate the frequency and types of CHD patterns in Turkish children with DS.

METHOD: The data relate to paediatric patients with DS who underwent cardiologic screening between 1994 and 2007 and were reviewed in our Paediatric Cardiology unit.

RESULTS: Four hundred and twenty-one out of the 1042 paediatric patients with DS studied over a 13-year period had associated CHD. Of these, 320 (77.6%) had a single cardiac lesion, while the remaining 92 patients (22.4%) had multiple defects. The most common single defect was an atrioventricular septal defect (AVSD) found in 141 patients (34.2%), followed by 69 patients (16.7%) showing secundum type atrial septal defect, and ventricular septal defect in 68 patients (16.5%). AVSDs were the leading type, isolated or combined with other cardiac anomalies with an overall occurrence of 19.8% of paediatric patients with DS, and 49.2% of paediatric patients with both DS and CHD.

CONCLUSION: This is the first study concerning the frequency and type of CHD observed in Turkish children with DS. The high frequency ofAVSD in Turkish children with DS implied that early screening for CHDs by echocardiography is crucial. The correction of AVSDs in paediatric patients with DS should be performed in the first 6 months of life to avoid irreversible haemodynamic consequences of the defect.

PMID: 19014001 [PubMed – in process]

Tonguing behaviours in persons with Down syndrome: Moderator of the effects of negative mood on behaviour problems.

J Intellect Dev Disabil. 2008 Dec

Barrett KC, Fidler DJ.
Colorado State University, Colorado, USA.

Background There is concern that tongue protrusion may be maladaptive in individuals with Down syndrome (DS). However, tonguing and other self-manipulatory behaviours have been shown to contribute to emotion regulation in children without disabilities.

Method Sixty individuals with intellectual disability (40 with DS, 20 of mixed aetiology) and their parents were videotaped during a puzzle-book task. Empirical relationships between observed tongue protrusion, other observed nonverbal behaviours, and reported negative mood, maladaptive behaviours, and stress-inducing characteristics were assessed.

Results Individuals with DS and reported negative mood who did not engage in tonguing were more likely to display internalising and externalising behaviours and stress-inducing characteristics, whereas those who did engage in tonguing were not more likely to display these characteristics.

Conclusion These findings are consistent with the possibility that tongue protrusion serves an emotion regulation function for individuals with DS.

Full Length Article – Informaworld

Parenting children with and without developmental delay: the role of self-mastery.

J Intellect Disabil Res. 2007 Jun

Paczkowski E, Baker BL.
UCLA, Los Angeles, CA 90095-1563, USA.

BACKGROUND: While parenting behaviours have direct effects on children’s behavioural outcomes, other, more distal factors also may be shaping the way a mother handles parenting responsibilities. Dispositional factors are likely to be a major influence in determining how one parents. Although researchers have studied the relationships among maternal dispositional factors, parenting, and child behaviours, few studies have examined these relationships when the child is at developmental risk. Children with developmental delays evidence elevated clinical level behaviour problems, so this group is of primary interest in the search for precursors to psychopathology. The present study examined how the maternal dispositional trait of self-mastery, as well as supportive and non-supportive parenting, relate to behaviour problems in young children with and without developmental delay.

METHOD: Participants were 225 families, drawn from Central Pennsylvania and Southern California. The children, all aged 4 years, were classified as delayed (n = 97) or non-delayed (n = 128). The Self-Mastery Scale measured perceived level of control over life events. The Coping with Children’s Negative Emotions Scale measured different ways parents perceive themselves as reacting to their children’s distress and negative affect. The Child Behavior Checklist assessed children’s behaviour problems.

RESULTS: Delayed condition mothers reported significantly more child behaviour problems than non-delayed condition mothers; the two conditions did not differ in self-mastery, supportive parenting, or non-supportive parenting. Self-mastery, non- supportive parenting reactions, and child behaviour problems all related significantly to one another. For the sample as a whole and within the delayed condition, the association between self-mastery and child behaviour problems was partially mediated by non-supportive parenting reactions, although self-mastery was still significantly associated with problem behaviour. In the non-delayed condition, although significant relationships also were found among the variables of interest, non-supportive parenting did not have a significant main or mediation effect. Delay status moderated the relationship between negative parenting reactions and child behaviour problems, assessed by the Child Behavior Checklist Total and Internalizing scores. When mothers displayed low levels of non-supportive reactions, children in the delayed and non-delayed groups had similar levels of total problem behaviour. However, when mothers were medium or high in non-supportive reactions, children in the delayed group had much higher levels of problem behaviours than those in the non-delayed group.

CONCLUSIONS: The present study extended research on parental dispositional factors and parenting by measuring self-mastery as a global personality trait rather than measuring self-efficacy related specifically to childrearing. Moreover, relationships were examined for both developmentally delayed and non-delayed samples, allowing for a clearer understanding of the influences on problem behaviours in children with developmental delays. The findings support the view that parenting behaviours have a greater impact on children at developmental risk.


Trisomy 21 and Down syndrome – A short review

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.


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.

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.

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.

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.

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.

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