Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer's disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge. Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the use of chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype–phenotype relationships in patients are likely to significantly contribute to the future understanding of DS.

INTRODUCTION

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). Approximately 0.45% of human conceptions are trisomic for Hsa21 (1). The incidence of trisomy is influenced by maternal age and differs between populations (between 1 in 319 and 1 in 1000 live births are trisomic for Hsa21) (26). Trisomic fetuses are at an elevated risk of miscarriage, and people with DS have an increased risk of developing several medical conditions (7). Recent advances in medical treatment and social inclusion have significantly increased the life expectancy of people with DS. In economically developed countries, the average life span of people who are trisomic for Hsa21 is now greater than 55 years (8). In this review, we will discuss novel findings in the understanding of DS and highlight future important avenues of research.

The additional copy of Hsa21, in people with DS, is proposed to result in the increased expression of many of the genes encoded on this chromosome. The imbalance in expression of Hsa21 and non-Hsa21 genes is hypothesized to result in the many phenotypes that characterize DS. However, only some of the Hsa21 genes are likely to be dosage-sensitive, such that the phenotype they confer is altered by gene-copy number. Thus to understand DS, it is crucial both to understand the genomic content of Hsa21 and to evaluate how the expression levels of these genes are altered by the presence of a third copy of Hsa21. There have been a number of recent advances in genomics relevant to DS. For example, the traditional definition of a gene has been modified (Box 1). A number of fusion transcripts that are encoded by two or more genes previously considered to be separate have been reported, such as the transcript encoded by exons from the Hsa21, DONSON and ATP50 genes (9). Whether these transcripts represent novel genes has yet to be determined. However, the number of genes recognized on Hsa21 is likely to continue to increase from the current count of more than 400 (10). In particular, as algorithms to identify non-coding RNAs (e.g. microRNAs) improve, the number of recognized genes may increase. Five microRNAs have been identified on Hsa21 (11,12). MicroRNAs regulate the expression of other genes (13), and their role in DS is not fully understood. Spatial and temporal mapping of the Hsa21 gene expression is also critical to the understanding of DS. The increase in expression of some Hsa21 genes caused by trisomy of Hsa21 has been recently shown to lie within the range of natural variations in the expression of these genes in the euploid population (14,15). Similar findings have also been reported in the Ts(1716)65Dn (Ts65Dn) mouse model of DS (Fig. 1) (16).

Figure 1.

Mouse models of Hsa21 trisomy and monosomy. Hsa21 (orange) is syntenic with regions of mouse chromosomes 16 (Mmu16, blue), 17 (Mmu 17, green) and 10 (Mmu10, grey). The Tc1 mouse model carries a freely segregating copy of Hsa21, which has two deleted regions, such that the model is trisomic for the majority of genes on Hsa21. The Dp1Yu, Ts65Dn, Ts1Cje and Ts1Rhr mouse models contain an additional copy of regions of mouse chromosome 16 that are syntenic with Hsa21, such that they are trisomic for a proportion of Hsa21 genes. The Ms1Rhr mouse model contains a deletion of a region of Mmu16; the Ms1Yah mouse model contains a deletion of a region of Mmu10. Hence, these models are monosomic for the genes in these deleted Hsa21 syntenic segments.

Figure 1.

Mouse models of Hsa21 trisomy and monosomy. Hsa21 (orange) is syntenic with regions of mouse chromosomes 16 (Mmu16, blue), 17 (Mmu 17, green) and 10 (Mmu10, grey). The Tc1 mouse model carries a freely segregating copy of Hsa21, which has two deleted regions, such that the model is trisomic for the majority of genes on Hsa21. The Dp1Yu, Ts65Dn, Ts1Cje and Ts1Rhr mouse models contain an additional copy of regions of mouse chromosome 16 that are syntenic with Hsa21, such that they are trisomic for a proportion of Hsa21 genes. The Ms1Rhr mouse model contains a deletion of a region of Mmu16; the Ms1Yah mouse model contains a deletion of a region of Mmu10. Hence, these models are monosomic for the genes in these deleted Hsa21 syntenic segments.

Box 1:What is a gene?

The definition of a gene has shifted over the past 100 years since it was first coined by Wilhelm Johannsen in 1909, based on the ideas of Mendel, de Vries, Correns and Tschermak. Their original theoretical definition of the gene being ‘the smallest unit of genetic inheritance’ remains the cornerstone of our understanding; however, the definition has grown with our knowledge of molecular biology. The gene has recently been defined as ‘a union of genomic sequences encoding a coherent set of potentially overlapping functional products’ (133). Splicing generates multiple transcripts from one gene. Moreover, exons from genes previously considered to be separate may be spliced together to generate novel transcripts (9). How to classify these fusion transcripts is a significant challenge. In addition, alternative transcription start sites that generate novel 5′ untranslated regions continue to be discovered, even for well-characterized genes (134). Although many of these novel transcripts are rare and their functional importance is not understood, our definition of a gene must encompass the observed diversity of the genome.

This suggests that these genes are unlikely to be candidates for the dosage-sensitive genes underlying DS phenotypes in the tissues investigated.

Trisomy of Hsa21 is associated with a small number of conserved features, occurring in all individuals, including mild-to-moderate learning disability, craniofacial abnormalities and hypotonia in early infancy (17). Although these phenotypes are always found in people with DS, the degree to which an individual is affected varies. Additionally, trisomy of Hsa21 is also associated with variant phenotypes that only affect some people with DS, including atrioventricular septal defects (AVSDs) in the heart, acute megakaryoblastic leukaemia (AMKL) and a decrease in the incidence of some solid tumours. This phenotypic variation is likely to be caused by a combination of environmental and genetic causes. Genetic polymorphisms in both Hsa21 and non-Hsa21 genes may account for much of this variation. Genome-wide association studies to identify these polymorphisms constitute a promising strategy to gain novel insights into the pathology of DS.

A central goal of DS research is to understand which of the genes on Hsa21, when present in three copies, lead to each of the different DS-associated phenotypes, and to elucidate how increased expression leads to the molecular, cellular and physiological changes underlying DS pathology. Two distinct approaches are being taken to address these issues. First, genomic association studies, such as that recently published by Lyle et al (18)., may point to genes that play an important role in pathology. Secondly, a number of animal models of Hsa21 trisomy have been generated. Recent advances in chromosome engineering have led to the establishment of mice trisomic for different sets of mouse genes syntenic to Hsa21, and a mouse strain, Tc(Hsa21)1TybEmcf (Tc1), carrying most of Hsa21, as a freely segregating chromosome (Fig. 1) (1927). These strains are being used both to map dosage-sensitive genes on Hsa21 and to understand pathological mechanisms. Here, we review recent advances in the understanding of DS-associated phenotypes and the development of therapeutic strategies to treat them.

RECENT ADVANCES IN UNDERSTANDING PHENOTYPES ASSOCIATED WITH DS

Development

Trisomy of Hsa21 has a significant impact on the development of many tissues, most notably the heart and the brain. A recent paper has suggested that trisomy of the Hsa21 genes, dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) and regulator of calcineurin 1 (RCAN1), may have an impact on the development of multiple tissues (28). DYRK1A is a priming kinase that facilitates the further phosphorylation of numerous proteins by other kinases (Fig. 2) (2938). It is up-regulated in a number of tissues from people with DS (39,40). RCAN1 is a regulator of the protein phosphatase calcineurin (41). Crabtree and colleagues hypothesized that trisomy of these two genes may act synergistically to alter signalling via the NFAT family of transcription factors (28). In an independent study, increased DYRK1A gene dosage was shown to decrease the expression level of RE1-silencing transcription factor (REST) (42). As REST is required both to maintain pluripotency and to facilitate neuronal differentiation, a perturbation in REST expression may alter the development of many cell types. Indeed, over-expression of DYRK1A in some animal models is associated with a number of phenotypes, including heart defects and abnormal learning and memory (28,33,4345). However, not all animal models that over-express DYRK1A exhibit these defects, suggesting that polymorphisms or differences in the expression of other genes influence the outcome of DYRK1A trisomy (24).

Figure 2.

Phosphorylation targets of DYRK1A. The Hsa21-encoded kinase DYRK1A has been shown to phosphorylate a multitude of targets, which have been implicated in a number of biological processes and DS-associated phenotypes, including endocytosis and AD.

Figure 2.

Phosphorylation targets of DYRK1A. The Hsa21-encoded kinase DYRK1A has been shown to phosphorylate a multitude of targets, which have been implicated in a number of biological processes and DS-associated phenotypes, including endocytosis and AD.

Trisomy of Hsa21 is associated with a reduction in brain volume, the size of the hippocampus and cerebellum being particularly affected (4649). A similar phenotype is also observed in the Ts65Dn model (50). Recent studies have started to elucidate the developmental mechanisms underlying these important phenotypes. Trisomic granule cell precursors from the cerebellum have a reduced mitogenic response to the morphogen sonic hedgehog (51). This was shown to underlie the reduced number of cerebellar granular cells observed in the Ts65Dn mouse model of DS. Hypocellularity in the hippocampus also has a developmental origin (52,53). Abnormalities in cell-cycle length, apoptosis and neocortical neurogenesis have been shown to contribute to this phenotype (5355). The reduced level of neurogenesis in Ts65Dn adult hippocampus can be ameliorated by treatment with the anti-depressant fluoxetine, which is a serotonin reuptake inhibitor (56). Fluoxetine may promote neurogenesis via a number of potential mechanisms, including a direct effect on serotonin levels or via an indirect effect on behaviour. Whether this drug has similar effect during embryonic development has yet to be determined.

Ts65Dn pups exhibit a delay in attaining several developmental milestones, such as forelimb grip and the righting reflex, mimicking the developmental delay observed in babies with DS (57). A recent report has demonstrated that treatment of Ts65Dn embryos with two neuroprotective peptides reduced the delay in achieving a number of sensory and motor developmental milestones during early post-natal development (58).

People with DS exhibit craniofacial dysmorphology, including a mandible of reduced size. This phenotype is also observed in the Ts65Dn and Tc1 models (26,59). In the Ts65Dn model, craniofacial dysmorphology is present from early post-natal development and may be related to specific changes in bone development (60,61). The small mandible in people with DS may be caused by migration and proliferation defects in mandible precursor (neural crest) cells in the developing embryo, related to an altered response to sonic hedgehog (62).

Learning and memory

All people with DS have a mild-to-moderate learning disability. Over-expression of a number of Hsa21 genes, including DYRK1A, synaptojanin 1 and single-minded homologue 2 (SIM2), results in learning and memory defects in mouse models, suggesting that trisomy of these genes may contribute to learning disability in people with DS (43,45,63,64). In addition, trisomy of neuronal channel proteins, such as G-protein-coupled inward-rectifying potassium channel subunit 2 (GIRK2), may also influence learning in people with DS (6567). Recent work has demonstrated that trisomy of a segment of mouse chromosome 16 (Mmu16) containing 33 genes including DYRK1A, GIRK2 and SIM2 was necessary, but not sufficient for the hippocampal-based learning deficits in the Ts65Dn mouse model (68). These data indicate that trisomy of multiple Hsa21 genes is required for the deficits in learning associated with DS. Moreover, Hsa21 trisomy may independently impact on multiple learning pathways.

Recent work on the Tc1 transchromosomic mouse model of DS has examined in detail the learning pathways affected by trisomy of Hsa21 (26,69). The Tc1 transchromosomic model exhibits abnormalities in short-term but not in long-term hippocampal-dependent learning. The learning deficits are correlated with specific abnormalities in long-term potentiation (LTP) in the dentate gyrus of the hippocampus. LTP is an electrophysiological process proposed to be the cellular basis of learning and memory (70). These data provide insight into which learning mechanisms may be affected by Hsa21 trisomy and can be used to further understand their genetic cause. Structural abnormalities may contribute to these deficits in learning and memory. Indeed, a correlation between specific synaptic abnormalities in the hippocampus of the Ts(16C-tel)1Cje (Ts1Cje) mouse and a defect in LTP has been reported (71). Moreover, a recent paper has demonstrated an alteration in the amounts of a number of synaptic components in the hippocampus of the Ts65Dn mouse (72).

Alzheimer's disease

People with DS have a greatly increased risk of early-onset Alzheimer's disease (AD). By the age of 60, between 50 and 70% of the people with DS develop dementia (7377). The known AD risk factor amyloid precursor protein (APP) is encoded on Hsa21. Trisomy of APP is likely to make a significant contribution to the increased frequency of dementia in people with DS. Indeed, triplication of a short segment of Hsa21 that includes APP in people without DS has been recently shown to be associated with early-onset AD. A number of features of neurodegeneration have been observed in mouse models of DS (7886). Loss of basal forebrain cholinergic neurons (BFCNs) occurs early in AD and also is observed in the Ts65Dn mouse model (87). Degeneration of BFCNs in Ts65Dn mice is dependent on trisomy of APP and is mediated by the effect of increased APP expression of retrograde axonal transport (83).

Hsa21 genes other than APP may also contribute to the early onset of AD in people with DS (33,34,40,8897). Indeed, the Ts1Cje mouse model, which is not trisomic for APP, exhibits tau hyperphosphorylation, an early sign of AD (98). Recent evidence suggests that trisomy of DYRK1A may contribute to the development of AD in people with DS. DYRK1A can phosphorylate Tau at a key priming site that permits its hyperphosphorylation (33,36,40,95). DYRK1A may also influence the alternative splicing of Tau and the phosphorylation of APP (34,99). A reduction in the level of protein phosphatase 2A and a decrease in the activity of α-secretase in the brains of people with DS have also been reported, both of which may contribute to AD in this population (94,100). Further studies are required to determine the identity of the trisomic genes that contribute to these phenotypes.

Heart defects

Trisomy of Hsa21 is associated with a number of congenital heart defects, the most common being AVSD that occurs in ∼20% of the people with DS (101). Mutations in the non-Hsa21 CRELD1 gene may contribute to the development of AVSD in DS (102). CRELD1 has also been linked to AVSDs by mapping the deletion breakpoints, on chromosome 3, in people with 3p-syndrome. Further studies are required to determine the identity of other genes that are important for heart development in people with DS. A number of Hsa21 trisomy mouse models exhibit heart defects similar to those observed in DS, suggesting that trisomy of one or more of the approximately 100 genes common to these models influences development of the heart (22,26,103,104).

Leukaemia and cancer

DS increases the risk of developing AMKL and acute lymphoblastic leukaemia (ALL). Approximately 10% of the DS newborns present with a transient myeloproliferative disorder (TMD), characterized by a clonal population of megakaryoblasts in the blood. This transient disease usually spontaneously resolves; however, 10–20% of the DS patients with TMD develop AMKL before 4 years of age (reviewed in 105). The development of TMD requires both trisomy 21 and mutations in the transcription factor GATA1 (106,107). It is likely that further mutations are required for TMD to develop into AMKL. The GATA1 mutations found in TMD and AMKL always have the same effect, causing translation to initiate at the second ATG of the coding region, leading to the production of a shorter protein, termed GATA1s. Trisomy of Hsa21 on its own, even in the absence of GATA1s, leads to an expansion of the megakaryocyte-erythroid progenitor population in fetal livers from human DS abortuses (108,109). These data suggest that trisomy of Hsa21 perturbs hematopoiesis, making megakaryocyte-erythroid progenitors susceptible to the effects of GATA1s, thereby promoting development of TMD. Several groups have reported the presence of mutations in Janus Kinase 3 (JAK3) in a small proportion of TMD/AMKL patients (110115). It was suggested that JAK3 inhibitors could be used as a therapy (111,114). However, both loss- and gain-of-function mutations have been found, so this may not be a viable treatment. Stem cell factor/KIT signalling has recently been demonstrated to stimulate TMD blast cell proliferation, and inhibitors of this pathway may be a treatment for severe TMD (116).

Attempts have been made to model these disorders in mice with a view to establishing which genes on Hsa21 need to be present in three copies in order to induce disease. A study of the Ts65Dn mouse model showed that it developed a late-onset myeloproliferative disorder, but did not develop leukaemia (117). It may be that the Ts65Dn model is not trisomic for the relevant dosage-sensitive genes required for the development of AMKL or that the expression of a mutant form of GATA1 will be required to increase the frequency of leukaemogenesis in this mouse model of DS.

The genetic events involved in DS-ALL are less well understood than those in DS-AMKL. A number of studies have reported DS-ALL cases with chromosomal abnormalities, gain-of-function mutations in JAK2 and submicroscopic deletions of genes including ETV6, CDKN2A and PAX5 (118121).

Although the incidence of leukaemia and cancer of the testis are increased in DS, the risk of developing most solid tumours is reduced (122,123). Crossing mouse models of DS with mice heterozygous for the Apcmin mutation reduced the number of tumours, which would normally accumulate in this model of colon cancer (124). Protection against the development of tumours required three copies of the Hsa21 ‘proto-oncogene’ Ets2, suggesting that in this context, Ets2 may be acting as a tumour suppressor (124).

Hypertension

People with DS have been reported to have a reduced incidence of hypertension (125,126). Trisomy of the Hsa21 microRNA hsa-miR-155 may contribute to this (12). Hsa-miR-155 is proposed to specifically target one allele of the type-1 angiotensin II receptor (AGTR1) gene, resulting in its under-expression, which may contribute to a reduced risk of hypertension. Further studies are required to validate this hypothesis and determine whether other genes may also protect people with DS against hypertension.

RECENT ADVANCES IN THERAPY AND FUTURE PROSPECTS

Recent interest in therapy for people with DS has focused on pharmacological treatment to enhance cognition. A number of compounds have been shown to improve learning in the Ts65Dn mouse model. Chronic treatment with picrotoxin or pentylenetetrazole improved hippocampal-based learning and LTP deficits in Ts65Dn mice, even after treatment had ceased (127). These compounds reduce gamma-aminobutyric acid-mediated inhibition in the hippocampus and are proposed to improve cognition by releasing normal learning from excess inhibition. Learning in Ts65Dn mice is also improved by the non-competitive N-methyl-D-aspartic acid receptor (NMDAR) antagonist, memantine (128). Memantine partially inhibits the opening of the NMDAR and is proposed to counter the effect of trisomy of RCAN1 on the function of the receptor. Further studies and clinical trials are required to further investigate the potential of these drugs to improve cognition in people who have DS.

To develop new therapeutic targets, it is necessary to determine the identity of genes that contribute to DS phenotypes. This requires a precise and standardized definition of phenotype. Ideally, these measurements should be formulated into a standardized protocol that can be applied at multiple centres, to permit sufficiently large numbers of samples for meaningful analysis to be collected. This can be facilitated by a carefully designed and curated biobank of detailed phenotypic data alongside DNA and tissue samples from participating individuals. These collections can then be used for both candidate gene and genome-wide analyses, by different investigators, permitting the identification of both dosage-sensitive trisomic Hsa21 and non-Hsa21 genes that contribute to DS phenotypes. Pooling of large data sets has led to recent important findings in the study of schizophrenia, diabetes and obesity, illustrating the importance of large-scale collaboration (129132). The careful collection of additional patient data will add much to our current understanding of DS.

As recent progress demonstrates, mouse models can be used in parallel with data collected from people with DS to test genetic associations, to explore biological mechanisms and to trial therapies. In addition to the long-standing Ts65Dn and Ts1Cje models, the newly developed mouse strains such as Tc1, Dp1Yu and Ts1Rhr have generated a range of models with distinct sets of trisomic genes (Fig. 1) (1927). Furthermore, the crossing of these strains with mice-bearing deletions of chromosomal segments syntenic to Hsa21, such as Ms1Yah and Ms1Rhr (Fig. 1), will allow systematic mapping and eventually identification of the dosage-sensitive genes causing DS-associated pathology.

DS was once thought to be an intractable condition because of the genetic complexity underlying it. Here, we have described recently reported breakthroughs in the understanding of Hsa21 trisomy, illustrating that research efforts in this field are making significant strides to understand and to develop treatments for the debilitating aspects of the syndrome. Many issues vital to the health and well-being of people with DS remain to be studied, making this an important and exciting time for Hsa21 trisomy research.

FUNDING

V.L.J.T. and K.A.A. are funded by the UK Medical Research Council, the EU, the Leukaemia Research Fund and the Wellcome Trust; F.K.W. and E.M.C.F. are funded by the UK Medical Research Council, the Wellcome Trust and the Fidelity Foundation.

ACKNOWLEDGEMENTS

We thank Roger Reeves, Dalia Kasperaviciute, Olivia Sheppard and Matilda Haas for advice on the manuscript and we thank Ray Young for help with preparation of the figures. We apologize to the many authors whose work we were unable to cite owing to space limitations.

Conflict of Interest statement. None declared.

REFERENCES

1
Hassold
T.
Abruzzo
M.
Adkins
K.
Griffin
D.
Merrill
M.
Millie
E.
Saker
D.
Shen
J.
Zaragoza
M.
Human aneuploidy: incidence, origin, and etiology
Environ. Mol. Mutagen.
 
1996
28
167
175
2
O'Nuallain
S.
Flanagan
O.
Raffat
I.
Avalos
G.
Dineen
B.
The prevalence of Down syndrome in County Galway
Ir. Med. J.
 
2007
100
329
331
3
Carothers
A.D.
Hecht
C.A.
Hook
E.B.
International variation in reported livebirth prevalence rates of Down syndrome, adjusted for maternal age
J. Med. Genet.
 
1999
36
386
393
4
Canfield
M.A.
Honein
M.A.
Yuskiv
N.
Xing
J.
Mai
C.T.
Collins
J.S.
Devine
O.
Petrini
J.
Ramadhani
T.A.
Hobbs
C.A.
et al.  
National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001
Birth Defects Res. A Clin. Mol. Teratol.
 
2006
76
747
756
5
Murthy
S.K.
Malhotra
A.K.
Mani
S.
Shara
M.E.
Al Rowaished
E.E.
Naveed
S.
Alkhayat
A.I.
Alali
M.T.
Incidence of Down syndrome in Dubai, UAE
Med. Princ. Pract.
 
2007
16
25
28
6
Wahab
A.A.
Bener
A.
Teebi
A.S.
The incidence patterns of Down syndrome in Qatar
Clin. Genet.
 
2006
69
360
362
7
Morris
J.K.
Wald
N.J.
Watt
H.C.
Fetal loss in Down syndrome pregnancies
Prenat. Diagn.
 
1999
19
142
145
8
Glasson
E.J.
Sullivan
S.G.
Hussain
R.
Petterson
B.A.
Montgomery
P.D.
Bittles
A.H.
The changing survival profile of people with Down's syndrome: implications for genetic counselling
Clin. Genet.
 
2002
62
390
393
9
Birney
E.
Stamatoyannopoulos
J.A.
Dutta
A.
Guigo
R.
Gingeras
T.R.
Margulies
E.H.
Weng
Z.
Snyder
M.
Dermitzakis
E.T.
Thurman
R.E.
et al.  
Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
Nature
 
2007
447
799
816
10
Gardiner
K.
Costa
A.C.
The proteins of human chromosome 21
Am. J. Med. Genet. C Semin. Med. Genet.
 
2006
142C
196
205
11
Kuhn
D.E.
Nuovo
G.J.
Martin
M.M.
Malana
G.E.
Pleister
A.P.
Jiang
J.
Schmittgen
T.D.
Terry
A.V.
Jr
Gardiner
K.
Head
E.
et al.  
Human chromosome 21-derived miRNAs are overexpressed in Down syndrome brains and hearts
Biochem. Biophys. Res. Commun.
 
2008
370
473
477
12
Sethupathy
P.
Borel
C.
Gagnebin
M.
Grant
G.R.
Deutsch
S.
Elton
T.S.
Hatzigeorgiou
A.G.
Antonarakis
S.E.
Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3’ untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes
Am. J. Hum. Genet.
 
2007
81
405
413
13
Bartel
D.P.
MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
 
2004
116
281
297
14
Prandini
P.
Deutsch
S.
Lyle
R.
Gagnebin
M.
Delucinge
V.C.
Delorenzi
M.
Gehrig
C.
Descombes
P.
Sherman
S.
Dagna
B.F.
et al.  
Natural gene-expression variation in Down syndrome modulates the outcome of gene–dosage imbalance
Am. J. Hum. Genet.
 
2007
81
252
263
15
Ait Yahya-Graison
E.
Aubert
J.
Dauphinot
L.
Rivals
I.
Prieur
M.
Golfier
G.
Rossier
J.
Personnaz
L.
Creau
N.
Blehaut
H.
et al.  
Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes
Am. J. Hum. Genet.
 
2007
81
475
491
16
Sultan
M.
Piccini
I.
Balzereit
D.
Herwig
R.
Saran
N.G.
Lehrach
H.
Reeves
R.H.
Yaspo
M.L.
Gene expression variation in Down's syndrome mice allows prioritization of candidate genes
Genome Biol.
 
2007
8
R91
17
Antonarakis
S.E.
Lyle
R.
Dermitzakis
E.T.
Reymond
A.
Deutsch
S.
Chromosome 21 and Down syndrome: from genomics to pathophysiology
Nat. Rev. Genet.
 
2004
5
725
738
18
Lyle
R.
Bena
F.
Gagos
S.
Gehrig
C.
Lopez
G.
Schinzel
A.
Lespinasse
J.
Bottani
A.
Dahoun
S.
Taine
L.
et al.  
Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21
Eur. J. Hum. Genet.
 
2008
advance online publication 12 November 2008; doi: 10.1038/ejhg.2008.214
19
Adams
D.J.
Biggs
P.J.
Cox
T.
Davies
R.
van der
W.L.
Jonkers
J.
Smith
J.
Plumb
B.
Taylor
R.
Nishijima
I.
et al.  
Mutagenic insertion and chromosome engineering resource (MICER)
Nat. Genet.
 
2004
36
867
871
20
Brault
V.
Besson
V.
Magnol
L.
Duchon
A.
Herault
Y.
Cre/loxP-mediated chromosome engineering of the mouse genome
Handb. Exp. Pharmacol.
 
2007
178
29
48
21
Duchon
A.
Besson
V.
Pereira
P.L.
Magnol
L.
Herault
Y.
Inducing segmental aneuploid mosaicism in the mouse through targeted asymmetric sister chromatid event of recombination
Genetics
 
2008
180
51
59
22
Li
Z.
Yu
T.
Morishima
M.
Pao
A.
LaDuca
J.
Conroy
J.
Nowak
N.
Matsui
S.
Shiraishi
I.
Yu
Y.E.
Duplication of the entire 22.9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities
Hum. Mol. Genet.
 
2007
16
1359
1366
23
Tybulewicz
V.L.
Fisher
E.M.
New techniques to understand chromosome dosage: mouse models of aneuploidy
Hum. Mol. Genet.
 
2006
15
Spec no. 2
R103
R109
24
Olson
L.E.
Richtsmeier
J.T.
Leszl
J.
Reeves
R.H.
A chromosome 21 critical region does not cause specific down syndrome phenotypes
Science
 
2004
306
687
690
25
Brault
V.
Pereira
P.
Duchon
A.
Herault
Y.
Modeling chromosomes in mouse to explore the function of genes, genomic disorders, and chromosomal organization
PLoS Genet.
 
2006
2
e86
26
O'Doherty
A.
Ruf
S.
Mulligan
C.
Hildreth
V.
Errington
M.L.
Cooke
S.
Sesay
A.
Modino
S.
Vanes
L.
Hernandez
D.
et al.  
An aneuploid mouse strain carrying human chromosome 21 with down syndrome phenotypes
Science
 
2005
309
2033
2037
27
Besson
V.
Brault
V.
Duchon
A.
Togbe
D.
Bizot
J.C.
Quesniaux
V.F.
Ryffel
B.
Herault
Y.
Modeling the monosomy for the telomeric part of human chromosome 21 reveals haploinsufficient genes modulating the inflammatory and airway responses
Hum. Mol. Genet.
 
2007
16
2040
2052
28
Arron
J.R.
Winslow
M.M.
Polleri
A.
Chang
C.P.
Wu
H.
Gao
X.
Neilson
J.R.
Chen
L.
Heit
J.J.
Kim
S.K.
et al.  
NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21
Nature
 
2006
441
595
600
29
de Graaf
K.
Hekerman
P.
Spelten
O.
Herrmann
A.
Packman
L.C.
Bussow
K.
Muller-Newen
G.
Becker
W.
Characterization of cyclin L2, a novel cyclin with an arginine/serine-rich domain: phosphorylation by DYRK1A and colocalization with splicing factors
J. Biol. Chem.
 
2004
279
4612
4624
30
de Graaf
K.
Czajkowska
H.
Rottmann
S.
Packman
L.C.
Lilischkis
R.
Luscher
B.
Becker
W.
The protein kinase DYRK1A phosphorylates the splicing factor SF3b1/SAP155 at Thr434, a novel in vivo phosphorylation site
BMC Biochem.
 
2006
7
7
31
Adayev
T.
Chen-Hwang
M.C.
Murakami
N.
Wang
R.
Hwang
Y.W.
MNB/DYRK1A phosphorylation regulates the interactions of synaptojanin 1 with endocytic accessory proteins
Biochem. Biophys. Res. Commun.
 
2006
351
1060
1065
32
Kim
E.J.
Sung
J.Y.
Lee
H.J.
Rhim
H.
Hasegawa
M.
Iwatsubo
T.
Min
d.S.
Kim
J.
Paik
S.R.
Chung
K.C.
Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation
J. Biol. Chem.
 
2006
281
33250
33257
33
Ryoo
S.R.
Jeong
H.K.
Radnaabazar
C.
Yoo
J.J.
Cho
H.J.
Lee
H.W.
Kim
I.S.
Cheon
Y.H.
Ahn
Y.S.
Chung
S.H.
et al.  
DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease
J. Biol. Chem.
 
2007
282
34850
34857
34
Ryoo
S.R.
Cho
H.J.
Lee
H.W.
Jeong
H.K.
Radnaabazar
C.
Kim
Y.S.
Kim
M.J.
Son
M.Y.
Seo
H.
Chung
S.H.
et al.  
Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer's disease
J. Neurochem.
 
2008
104
1333
1344
35
Huang
Y.
Chen-Hwang
M.C.
Dolios
G.
Murakami
N.
Padovan
J.C.
Wang
R.
Hwang
Y.W.
Mnb/Dyrk1A phosphorylation regulates the interaction of dynamin 1 with SH3 domain-containing proteins
Biochemistry
 
2004
43
10173
10185
36
Woods
Y.L.
Cohen
P.
Becker
W.
Jakes
R.
Goedert
M.
Wang
X.
Proud
C.G.
The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase
Biochem. J.
 
2001
355
609
615
37
Aranda
S.
Alvarez
M.
Turro
S.
Laguna
A.
de la
L.S.
Sprouty2-mediated inhibition of fibroblast growth factor signaling is modulated by the protein kinase DYRK1A
Mol. Cell. Biol.
 
2008
28
5899
5911
38
Gwack
Y.
Sharma
S.
Nardone
J.
Tanasa
B.
Iuga
A.
Srikanth
S.
Okamura
H.
Bolton
D.
Feske
S.
Hogan
P.G.
et al.  
A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT
Nature
 
2006
441
646
650
39
Dowjat
W.K.
Adayev
T.
Kuchna
I.
Nowicki
K.
Palminiello
S.
Hwang
Y.W.
Wegiel
J.
Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome
Neurosci. Lett.
 
2007
413
77
81
40
Liu
F.
Liang
Z.
Wegiel
J.
Hwang
Y.W.
Iqbal
K.
Grundke-Iqbal
I.
Ramakrishna
N.
Gong
C.X.
Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome
FASEB J.
 
2008
22
3224
3233
41
Fuentes
J.J.
Genesca
L.
Kingsbury
T.J.
Cunningham
K.W.
Perez-Riba
M.
Estivill
X.
de la
L.S.
DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways
Hum. Mol. Genet.
 
2000
9
1681
1690
42
Canzonetta
C.
Mulligan
C.
Deutsch
S.
Ruf
S.
O'Doherty
A.
Lyle
R.
Borel
C.
Lin-Marq
N.
Delom
F.
Groet
J.
et al.  
DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome
Am. J. Hum. Genet.
 
2008
83
388
400
43
Altafaj
X.
Dierssen
M.
Baamonde
C.
Marti
E.
Visa
J.
Guimera
J.
Oset
M.
Gonzalez
J.R.
Florez
J.
Fillat
C.
et al.  
Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome
Hum. Mol. Genet.
 
2001
10
1915
1923
44
Martinez
D.L.
Altafaj
X.
Gallego
X.
Marti
E.
Estivill
X.
Sahun
I.
Fillat
C.
Dierssen
M.
Motor phenotypic alterations in TgDyrk1a transgenic mice implicate DYRK1A in Down syndrome motor dysfunction
Neurobiol. Dis.
 
2004
15
132
142
45
Ahn
K.J.
Jeong
H.K.
Choi
H.S.
Ryoo
S.R.
Kim
Y.J.
Goo
J.S.
Choi
S.Y.
Han
J.S.
Ha
I.
Song
W.J.
DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects
Neurobiol. Dis.
 
2006
22
463
472
46
Weis
S.
Weber
G.
Neuhold
A.
Rett
A.
Down syndrome: MR quantification of brain structures and comparison with normal control subjects
AJNR Am. J. Neuroradiol.
 
1991
12
1207
1211
47
Aylward
E.H.
Habbak
R.
Warren
A.C.
Pulsifer
M.B.
Barta
P.E.
Jerram
M.
Pearlson
G.D.
Cerebellar volume in adults with Down syndrome
Arch. Neurol.
 
1997
54
209
212
48
Pearlson
G.D.
Breiter
S.N.
Aylward
E.H.
Warren
A.C.
Grygorcewicz
M.
Frangou
S.
Barta
P.E.
Pulsifer
M.B.
MRI brain changes in subjects with Down syndrome with and without dementia
Dev. Med. Child Neurol.
 
1998
40
326
334
49
Aylward
E.H.
Li
Q.
Honeycutt
N.A.
Warren
A.C.
Pulsifer
M.B.
Barta
P.E.
Chan
M.D.
Smith
P.D.
Jerram
M.
Pearlson
G.D.
MRI volumes of the hippocampus and amygdala in adults with Down's syndrome with and without dementia
Am. J. Psychiatry
 
1999
156
564
568
50
Aldridge
K.
Reeves
R.H.
Olson
L.E.
Richtsmeier
J.T.
Differential effects of trisomy on brain shape and volume in related aneuploid mouse models
Am. J. Med. Genet. A
 
2007
143A
1060
1070
51
Roper
R.J.
Baxter
L.L.
Saran
N.G.
Klinedinst
D.K.
Beachy
P.A.
Reeves
R.H.
Defective cerebellar response to mitogenic Hedgehog signaling in Down syndrome mice
Proc. Natl Acad. Sci. USA
 
2006
103
1452
1456
52
Lorenzi
H.A.
Reeves
R.H.
Hippocampal hypocellularity in the Ts65Dn mouse originates early in development
Brain Res.
 
2006
1104
153
159
53
Guidi
S.
Bonasoni
P.
Ceccarelli
C.
Santini
D.
Gualtieri
F.
Ciani
E.
Bartesaghi
R.
Neurogenesis impairment and increased cell death reduce total neuron number in the hippocampal region of fetuses with Down syndrome
Brain Pathol.
 
2008
18
180
197
54
Lorenzi
H.A.
Reeves
R.H.
Hippocampal hypocellularity in the Ts65Dn mouse originates early in development
Brain Res.
 
2006
1104
153
159
55
Contestabile
A.
Fila
T.
Ceccarelli
C.
Bonasoni
P.
Bonapace
L.
Santini
D.
Bartesaghi
R.
Ciani
E.
Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with Down syndrome and in Ts65Dn mice
Hippocampus
 
2007
17
665
678
56
Clark
S.
Schwalbe
J.
Stasko
M.R.
Yarowsky
P.J.
Costa
A.C.
Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome
Exp. Neurol.
 
2006
200
256
261
57
Holtzman
D.M.
Santucci
D.
Kilbridge
J.
Chua-Couzens
J.
Fontana
D.J.
Daniels
S.E.
Johnson
R.M.
Chen
K.
Sun
Y.
Carlson
E.
et al.  
Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome
Proc. Natl Acad. Sci. USA
 
1996
93
13333
13338
58
Toso
L.
Cameroni
I.
Roberson
R.
Abebe
D.
Bissell
S.
Spong
C.Y.
Prevention of developmental delays in a Down syndrome mouse model
Obstet. Gynecol.
 
2008
112
1242
1251
59
Richtsmeier
J.T.
Baxter
L.L.
Reeves
R.H.
Parallels of craniofacial maldevelopment in Down syndrome and Ts65Dn mice
Dev. Dyn.
 
2000
217
137
145
60
Hill
C.A.
Reeves
R.H.
Richtsmeier
J.T.
Effects of aneuploidy on skull growth in a mouse model of Down syndrome
J Anat.
 
2007
210
394
405
61
Parsons
T.
Ryan
T.M.
Reeves
R.H.
Richtsmeier
J.T.
Microstructure of trabecular bone in a mouse model for Down syndrome
Anat. Rec. (Hoboken.)
 
2007
290
414
421
62
Roper
R.J.
Vanhorn
J.F.
Cain
C.C.
Reeves
R.H.
A neural crest deficit in Down syndrome mice is associated with deficient mitotic response to Sonic hedgehog
Mech. Dev
 
2008
Published online 21 November, doi: 10.1016/j.mod.2008.11.002
63
Voronov
S.V.
Frere
S.G.
Giovedi
S.
Pollina
E.A.
Borel
C.
Zhang
H.
Schmidt
C.
Akeson
E.C.
Wenk
M.R.
Cimasoni
L.
et al.  
Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome
Proc. Natl Acad. Sci. USA
 
2008
105
9415
9420
64
Meng
X.
Peng
B.
Shi
J.
Zheng
Y.
Chen
H.
Zhang
J.
Li
L.
Zhang
C.
Effects of overexpression of Sim2 on spatial memory and expression of synapsin I in rat hippocampus
Cell Biol. Int.
 
2006
30
841
847
65
Best
T.K.
Cho-Clark
M.
Siarey
R.J.
Galdzicki
Z.
Speeding of miniature excitatory post-synaptic currents in Ts65Dn cultured hippocampal neurons
Neurosci. Lett.
 
2008
438
356
361
66
Best
T.K.
Siarey
R.J.
Galdzicki
Z.
Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current
J. Neurophysiol.
 
2007
97
892
900
67
Harashima
C.
Jacobowitz
D.M.
Witta
J.
Borke
R.C.
Best
T.K.
Siarey
R.J.
Galdzicki
Z.
Abnormal expression of the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) in hippocampus, frontal cortex, and substantia nigra of Ts65Dn mouse: a model of Down syndrome
J. Comp. Neurol.
 
2006
494
815
833
68
Olson
L.E.
Roper
R.J.
Sengstaken
C.L.
Peterson
E.A.
Aquino
V.
Galdzicki
Z.
Siarey
R.
Pletnikov
M.
Moran
T.H.
Reeves
R.H.
Trisomy for the Down syndrome ‘critical region’ is necessary but not sufficient for brain phenotypes of trisomic mice
Hum. Mol. Genet.
 
2007
16
774
782
69
Morice
E.
Andreae
L.C.
Cooke
S.F.
Vanes
L.
Fisher
E.M.
Tybulewicz
V.L.
Bliss
T.V.
Preservation of long-term memory and synaptic plasticity despite short-term impairments in the Tc1 mouse model of Down syndrome
Learn. Mem.
 
2008
15
492
500
70
Bliss
T.V.
Lomo
T.
Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path
J. Physiol.
 
1973
232
331
356
71
Belichenko
P.V.
Kleschevnikov
A.M.
Salehi
A.
Epstein
C.J.
Mobley
W.C.
Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype–phenotype relationships
J. Comp. Neurol.
 
2007
504
329
345
72
Belichenko
P.V.
Kleschevnikov
A.M.
Masliah
E.
Wu
C.
Takimoto-Kimura
R.
Salehi
A.
Mobley
W.C.
Excitatory–inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of down syndrome
J. Comp. Neurol.
 
2008
512
453
466
73
Holland
A.J.
Hon
J.
Huppert
F.A.
Stevens
F.
Incidence and course of dementia in people with Down's syndrome: findings from a population-based study
J. Intellect. Disabil. Res.
 
2000
44
138
146
74
Holland
A.J.
Hon
J.
Huppert
F.A.
Stevens
F.
Watson
P.
Population-based study of the prevalence and presentation of dementia in adults with Down's syndrome
Br. J. Psychiatry
 
1998
172
493
498
75
Janicki
M.P.
Dalton
A.J.
Prevalence of dementia and impact on intellectual disability services
Ment. Retard.
 
2000
38
276
288
76
Johannsen
P.
Christensen
J.E.
Mai
J.
The prevalence of dementia in Down syndrome
Dementia
 
1996
7
221
225
77
Lai
F.
Williams
R.S.
A prospective study of Alzheimer disease in Down syndrome
Arch. Neurol.
 
1989
46
849
853
78
Granholm
A.C.
Sanders
L.A.
Crnic
L.S.
Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down's syndrome
Exp. Neurol.
 
2000
161
647
663
79
Granholm
A.C.
Ford
K.A.
Hyde
L.A.
Bimonte
H.A.
Hunter
C.L.
Nelson
M.
Albeck
D.
Sanders
L.A.
Mufson
E.J.
Crnic
L.S.
Estrogen restores cognition and cholinergic phenotype in an animal model of Down syndrome
Physiol. Behav.
 
2002
77
371
385
80
Hunter
C.L.
Bimonte
H.A.
Granholm
A.C.
Behavioral comparison of 4 and 6 month-old Ts65Dn mice: age-related impairments in working and reference memory
Behav. Brain Res.
 
2003
138
121
131
81
Hunter
C.L.
Bachman
D.
Granholm
A.C.
Minocycline prevents cholinergic loss in a mouse model of Down's syndrome
Ann. Neurol.
 
2004
56
675
688
82
Necchi
D.
Lomoio
S.
Scherini
E.
Axonal abnormalities in cerebellar Purkinje cells of the Ts65Dn mouse
Brain Res.
 
2008
1238
181
188
83
Salehi
A.
Delcroix
J.D.
Belichenko
P.V.
Zhan
K.
Wu
C.
Valletta
J.S.
Takimoto-Kimura
R.
Kleschevnikov
A.M.
Sambamurti
K.
Chung
P.P.
et al.  
Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration
Neuron
 
2006
51
29
42
84
Cooper
J.D.
Salehi
A.
Delcroix
J.D.
Howe
C.L.
Belichenko
P.V.
Chua-Couzens
J.
Kilbridge
J.F.
Carlson
E.J.
Epstein
C.J.
Mobley
W.C.
Failed retrograde transport of NGF in a mouse model of Down's syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion
Proc. Natl Acad. Sci. USA
 
2001
98
10439
10444
85
Seo
H.
Isacson
O.
Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice
Exp. Neurol.
 
2005
193
469
480
86
Holtzman
D.M.
Li
Y.
Chen
K.
Gage
F.H.
Epstein
C.J.
Mobley
W.C.
Nerve growth factor reverses neuronal atrophy in a Down syndrome model of age-related neurodegeneration
Neurology
 
1993
43
2668
2673
87
Mann
D.M.
Yates
P.O.
Marcyniuk
B.
Ravindra
C.R.
Pathological evidence for neurotransmitter deficits in Down's syndrome of middle age
J. Ment. Defic. Res.
 
1985
29
125
135
88
Porta
S.
Serra
S.A.
Huch
M.
Valverde
M.A.
Llorens
F.
Estivill
X.
Arbones
M.L.
Marti
E.
RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration
Hum. Mol. Genet.
 
2007
16
1039
1050
89
Ermak
G.
Morgan
T.E.
Davies
K.J.
Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease
J. Biol. Chem.
 
2001
276
38787
38794
90
Ermak
G.
Davies
K.J.
DSCR1(Adapt78)—a Janus gene providing stress protection but causing Alzheimer's disease?
IUBMB Life
 
2003
55
29
31
91
Ermak
G.
Harris
C.D.
Battocchio
D.
Davies
K.J.
RCAN1 (DSCR1 or Adapt78) stimulates expression of GSK-3beta
FEBS J.
 
2006
273
2100
2109
92
Lee
J.H.
Chulikavit
M.
Pang
D.
Zigman
W.B.
Silverman
W.
Schupf
N.
Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome
Neurosci. Lett.
 
2007
425
105
109
93
Kimura
R.
Kamino
K.
Yamamoto
M.
Nuripa
A.
Kida
T.
Kazui
H.
Hashimoto
R.
Tanaka
T.
Kudo
T.
Yamagata
H.
et al.  
The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease
Hum. Mol. Genet.
 
2007
16
15
23
94
Liang
Z.
Liu
F.
Iqbal
K.
Grundke-Iqbal
I.
Wegiel
J.
Gong
C.X.
Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome
J. Alzheimers Dis.
 
2008
13
295
302
95
Park
J.
Yang
E.J.
Yoon
J.H.
Chung
K.C.
Dyrk1A overexpression in immortalized hippocampal cells produces the neuropathological features of Down syndrome
Mol. Cell. Neurosci.
 
2007
36
270
279
96
Wegiel
J.
Dowjat
K.
Kaczmarski
W.
Kuchna
I.
Nowicki
K.
Frackowiak
J.
Mazur
K.B.
Wegiel
J.
Silverman
W.P.
Reisberg
B.
et al.  
The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome
Acta Neuropathol.
 
2008
116
391
407
97
Shi
J.
Zhang
T.
Zhou
C.
Chohan
M.O.
Gu
X.
Wegiel
J.
Zhou
J.
Hwang
Y.W.
Iqbal
K.
Grundke-Iqbal
I.
et al.  
Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of Tau in Down syndrome
J. Biol. Chem.
 
2008
283
28660
28669
98
Shukkur
E.A.
Shimohata
A.
Akagi
T.
Yu
W.
Yamaguchi
M.
Murayama
M.
Chui
D.
Takeuchi
T.
Amano
K.
Subramhanya
K.H.
et al.  
Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome
Hum. Mol. Genet.
 
2006
15
2752
2762
99
Shi
J.
Zhang
T.
Zhou
C.
Chohan
M.O.
Gu
X.
Wegiel
J.
Zhou
J.
Hwang
Y.W.
Iqbal
K.
Grundke-Iqbal
I.
et al.  
Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of Tau in Down syndrome
J. Biol. Chem.
 
2008
283
28660
28669
100
Nistor
M.
Don
M.
Parekh
M.
Sarsoza
F.
Goodus
M.
Lopez
G.E.
Kawas
C.
Leverenz
J.
Doran
E.
Lott
I.T.
et al.  
Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain
Neurobiol. Aging
 
2007
28
1493
1506
101
Freeman
S.B.
Bean
L.H.
Allen
E.G.
Tinker
S.W.
Locke
A.E.
Druschel
C.
Hobbs
C.A.
Romitti
P.A.
Royle
M.H.
Torfs
C.P.
et al.  
Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project
Genet. Med.
 
2008
10
173
180
102
Maslen
C.L.
Babcock
D.
Robinson
S.W.
Bean
L.J.
Dooley
K.J.
Willour
V.L.
Sherman
S.L.
CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome
Am. J. Med. Genet. A
 
2006
140
2501
2505
103
Moore
C.S.
Postnatal lethality and cardiac anomalies in the Ts65Dn Down syndrome mouse model
Mamm. Genome
 
2006
17
1005
1012
104
Williams
A.D.
Mjaatvedt
C.H.
Moore
C.S.
Characterization of the cardiac phenotype in neonatal Ts65Dn mice
Dev. Dyn.
 
2008
237
426
435
105
Izraeli
S.
Rainis
L.
Hertzberg
L.
Smooha
G.
Birger
Y.
Trisomy of chromosome 21 in leukemogenesis
Blood Cells Mol. Dis.
 
2007
39
156
159
106
Groet
J.
McElwaine
S.
Spinelli
M.
Rinaldi
A.
Burtscher
I.
Mulligan
C.
Mensah
A.
Cavani
S.
Dagna-Bricarelli
F.
Basso
G.
et al.  
Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder
Lancet
 
2003
361
1617
1620
107
Wechsler
J.
Greene
M.
McDevitt
M.A.
Anastasi
J.
Karp
J.E.
Le Beau
M.M.
Crispino
J.D.
Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome
Nat. Genet.
 
2002
32
148
152
108
Chou
S.T.
Opalinska
J.B.
Yao
Y.
Fernandes
M.A.
Kalota
A.
Brooks
J.S.
Choi
J.K.
Gewirtz
A.M.
Danet-Desnoyers
G.A.
Nemiroff
R.L.
et al.  
Trisomy 21 enhances human fetal erythro-megakaryocytic development
Blood
 
2008
112
4503
4506
109
Tunstall-Pedoe
O.
Roy
A.
Karadimitris
A.
de la
F.J.
Fisk
N.M.
Bennett
P.
Norton
A.
Vyas
P.
Roberts
I.
Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations
Blood
 
2008
112
4507
4511
110
Malinge
S.
Ragu
C.
Della-Valle
V.
Pisani
D.
Constantinescu
S.N.
Perez
C.
Villeval
J.L.
Reinhardt
D.
Landman-Parker
J.
Michaux
L.
et al.  
Activating mutations in human acute megakaryoblastic leukemia
Blood
 
2008
112
4220
4226
111
Sato
T.
Toki
T.
Kanezaki
R.
Xu
G.
Terui
K.
Kanegane
H.
Miura
M.
Adachi
S.
Migita
M.
Morinaga
S.
et al.  
Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome
Br. J. Haematol.
 
2008
141
681
688
112
Klusmann
J.H.
Reinhardt
D.
Hasle
H.
Kaspers
G.J.
Creutzig
U.
Hahlen
K.
van den Heuvel-Eibrink
M.M.
Zwaan
C.M.
Janus kinase mutations in the development of acute megakaryoblastic leukemia in children with and without Down's syndrome
Leukemia
 
2007
21
1584
1587
113
Kiyoi
H.
Yamaji
S.
Kojima
S.
Naoe
T.
JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults
Leukemia
 
2007
21
574
576
114
Walters
D.K.
Mercher
T.
Gu
T.L.
O'Hare
T.
Tyner
J.W.
Loriaux
M.
Goss
V.L.
Lee
K.A.
Eide
C.A.
Wong
M.J.
et al.  
Activating alleles of JAK3 in acute megakaryoblastic leukemia
Cancer Cell
 
2006
10
65
75
115
De Vita
S.
Mulligan
C.
McElwaine
S.
Dagna-Bricarelli
F.
Spinelli
M.
Basso
G.
Nizetic
D.
Groet
J.
Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome
Br. J. Haematol.
 
2007
137
337
341
116
Toki
T.
Kanezaki
R.
Adachi
S.
Fujino
H.
Xu
G.
Sato
T.
Suzuki
K.
Tauchi
H.
Endo
M.
Ito
E.
The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia
Leukemia
 
2008
advance online publication 2 October 2008; doi: 10.1038/leu.2008.267
117
Kirsammer
G.
Jilani
S.
Liu
H.
Davis
E.
Gurbuxani
S.
Le Beau
M.M.
Crispino
J.D.
Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome
Blood
 
2008
111
767
775
118
Forestier
E.
Izraeli
S.
Beverloo
B.
Haas
O.
Pession
A.
Michalova
K.
Stark
B.
Harrison
C.J.
Teigler-Schlegel
A.
Johansson
B.
Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study
Blood
 
2008
111
1575
1583
119
Malinge
S.
Ben Abdelali
R.
Settegrana
C.
Radford-Weiss
I.
Debre
M.
Beldjord
K.
Macintyre
E.A.
Villeval
J.L.
Vainchenker
W.
Berger
R.
et al.  
Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia
Blood
 
2007
109
2202
2204
120
Kearney
L.
Gonzalez
D.C.
Yeung
J.
Procter
J.
Horsley
S.W.
Eguchi-Ishimae
M.
Bateman
C.M.
Anderson
K.
Chaplin
T.
Young
B.D.
et al.  
A specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukaemia
Blood
 
2008
prepublished online 16 October 2008, doi:10.1182/blood-2008-08-170928
121
Bercovich
D.
Ganmore
I.
Scott
L.M.
Wainreb
G.
Birger
Y.
Elimelech
A.
Shochat
C.
Cazzaniga
G.
Biondi
A.
Basso
G.
et al.  
Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome
Lancet
 
2008
372
1484
1492
122
Hasle
H.
Pattern of malignant disorders in individuals with Down's syndrome
Lancet Oncol.
 
2001
2
429
436
123
Yang
Q.
Rasmussen
S.A.
Friedman
J.M.
Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study
Lancet
 
2002
359
1019
1025
124
Sussan
T.E.
Yang
A.
Li
F.
Ostrowski
M.C.
Reeves
R.H.
Trisomy represses Apc(Min)-mediated tumours in mouse models of Down's syndrome
Nature
 
2008
451
73
75
125
Morrison
R.A.
McGrath
A.
Davidson
G.
Brown
J.J.
Murray
G.D.
Lever
A.F.
Low blood pressure in Down's syndrome, a link with Alzheimer's disease?
Hypertension
 
1996
28
569
575
126
Draheim
C.C.
McCubbin
J.A.
Williams
D.P.
Differences in cardiovascular disease risk between nondiabetic adults with mental retardation with and without Down syndrome
Am. J. Ment. Retard.
 
2002
107
201
211
127
Fernandez
F.
Morishita
W.
Zuniga
E.
Nguyen
J.
Blank
M.
Malenka
R.C.
Garner
C.C.
Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome
Nat. Neurosci.
 
2007
10
411
413
128
Costa
A.C.
Scott-McKean
J.J.
Stasko
M.R.
Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test
Neuropsychopharmacology
 
2008
33
1624
1632
129
Saxena
R.
Voight
B.F.
Lyssenko
V.
Burtt
N.P.
de Bakker
P.I.
Chen
H.
Roix
J.J.
Kathiresan
S.
Hirschhorn
J.N.
Daly
M.J.
et al.  
Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
Science
 
2007
316
1331
1336
130
Loos
R.J.
Lindgren
C.M.
Li
S.
Wheeler
E.
Zhao
J.H.
Prokopenko
I.
Inouye
M.
Freathy
R.M.
Attwood
A.P.
Beckmann
J.S.
et al.  
Common variants near MC4R are associated with fat mass, weight and risk of obesity
Nat. Genet.
 
2008
40
768
775
131
O'Donovan
M.C.
Craddock
N.
Norton
N.
Williams
H.
Peirce
T.
Moskvina
V.
Nikolov
I.
Hamshere
M.
Carroll
L.
Georgieva
L.
et al.  
Identification of loci associated with schizophrenia by genome-wide association and follow-up
Nat. Genet.
 
2008
40
1053
1055
132
Stefansson
H.
Rujescu
D.
Cichon
S.
Pietilainen
O.P.
Ingason
A.
Steinberg
S.
Fossdal
R.
Sigurdsson
E.
Sigmundsson
T.
Buizer-Voskamp
J.E.
et al.  
Large recurrent microdeletions associated with schizophrenia
Nature
 
2008
455
232
236
133
Gerstein
M.B.
Bruce
C.
Rozowsky
J.S.
Zheng
D.
Du
J.
Korbel
J.O.
Emanuelsson
O.
Zhang
Z.D.
Weissman
S.
Snyder
M.
What is a gene, post-ENCODE? History and updated definition
Genome Res.
 
2007
17
669
681
134
Denoeud
F.
Kapranov
P.
Ucla
C.
Frankish
A.
Castelo
R.
Drenkow
J.
Lagarde
J.
Alioto
T.
Manzano
C.
Chrast
J.
et al.  
Prominent use of distal 5’ transcription start sites and discovery of a large number of additional exons in ENCODE regions
Genome Res.
 
2007
17
746
759
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