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Down syndrome--recent progress and future prospects.

Wiseman FK, Alford KA, Tybulewicz VL, Fisher EM - Hum. Mol. Genet. (2009)

Bottom Line: Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London, UK. f.wiseman@prion.ucl.ac.uk

ABSTRACT
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.

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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.
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DDP010F2: 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.

Mentions: 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) (29–38). 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 (28,33,43–45). 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).


Down syndrome--recent progress and future prospects.

Wiseman FK, Alford KA, Tybulewicz VL, Fisher EM - Hum. Mol. Genet. (2009)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2657943&req=5

DDP010F2: 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.
Mentions: 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) (29–38). 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 (28,33,43–45). 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).

Bottom Line: Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London, UK. f.wiseman@prion.ucl.ac.uk

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus