Trends in Molecular Medicine
Update
Research FocusCooperation to amplify gene-dosage-imbalance effects
Research Focus
Section snippets
Trisomy 21 and Down syndrome: genotype and phenotype
Humans have two copies of each of the 23 autosomic chromosomes in all their somatic cells. In some genetic abnormalities that are known as trisomies, an extra chromosome is present due to defective chromosome segregation during germ-cell meiosis. Trisomy of human chromosome 21 (HSA21) is the most common trisomy at birth, the only one for which individuals survive beyond childhood and the cause of a developmental and dysmorphic disorder known as Down syndrome (DS).
The clinical presentation of DS
From gene-dosage imbalance to pathology
The presence of an extra copy of HSA21 genes predicts an increased expression of ∼1.5-fold at the RNA level for those genes in trisomy. Experiments in which this effect has been evaluated indicate that this is indeed the case for most HSA21 genes in DS samples and for their orthologs in mouse trisomic models [3]. In the simplest scenario, the overexpression of one specific gene would lead to the disturbance of a biological process and, as a result, a single gene would be responsible for each
A novel altered pathway in Down syndrome
A clear example of a cooperative interaction between two HSA21 genes on a signaling pathway has recently been presented for the nuclear factor of activated T cells (NFAT) pathway (see Glossary), as the result of the collaborative effort of several groups at Stanford University and the Genetic Engineering Unit at Kyoto University [4].
NFAT transcription factors are well-known regulators of development and normal physiology in mammals [5]. Their activity is controlled by cycles of
DSCR1 and DYRK1A cooperation on NFAT signaling pathways
The recent report by Arron et al. [4] has elegantly combined phenotypic analysis of mouse models, signaling-pathway biochemistry and mathematics to model perturbations of gene networks. These authors undertook a systematic analysis of DS-related phenotypes in mice that were engineered not to express one or several NFAT family members or to lack calcineurin activity. The presence of DS-like phenotypes in these mice led the authors to conclude that reduced NFAT activity might be implicated in the
The long road towards Down-syndrome therapeutics
There is no doubt that the development of new therapies would greatly improve the quality of life of people with DS. However, the issue is far from simple. First, many of the pathological traits of DS are likely to be linked to the alteration of pathways that are required for normal embryonic development, as would be the case for some of the phenotypes related to disturbances in NFAT signaling. Therefore, restoration of normality would require a precise definition of the appropriate
Concluding remarks
Trisomy 21 is considered to be a model for human disorders involving gene-dosage imbalance. In the 1990s, research on HSA21 contributed greatly to the development of many technical tools used during the genomic era. Consequently, HSA21 was one of the first human chromosomes to be completely sequenced (Box 1). Over the past few years, DS research has moved into the transcriptomic era, and a large amount of data on changes in RNA expression has being collected both for HSA21 genes and for the
Acknowledgements
S.L. acknowledges support from the Spanish MEC (BFU2004–01768). We thank S. Bartlett for his linguistic help.
Glossary
- Calcineurin (also known as protein phosphatase 2B)
- it is an enzyme that catalyzes the dephosphorylation of phosphorylated serine–threonine residues in proteins, and the only phosphatase that is regulated by Ca2+. Calcineurin is involved in the regulation of many cellular processes, including cardiac hypertrophy, skeletal-muscle development, synaptic plasticity and T-cell activation. In this regard, calcineurin is the main target of the immunosuppressive drugs cyclosporine A and FK506.
- DSCR1
- it
References (18)
NFAT signaling in vertebrate development
Curr. Opin. Genet. Dev.
(2001)Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis
J. Biol. Chem.
(2004)Down syndrome (Trisomy 21)
Chromosome 21 and Down syndrome: from genomics to pathophysiology
Nat. Rev. Genet.
(2004)Transcriptional disruptions in Down syndrome: a case study in the Ts1Cje mouse cerebellum during post-natal development
J. Neurochem.
(2006)NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21
Nature
(2006)Transcriptional regulation by calcium, calcineurin, and NFAT
Genes Dev.
(2003)DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways
Hum. Mol. Genet.
(2000)The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin
Nat. Immunol.
(2003)
Cited by (15)
Down Syndrome
2013, Neural Circuit Development and Function in the Healthy and Diseased Brain: Comprehensive Developmental NeuroscienceDown Syndrome
2013, Neural Circuit Development and Function in the Heathy and Diseased BrainRegulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation
2011, Journal of Biological ChemistryCitation Excerpt :A previous study identified the C-terminal 57 residues of RCAN1 that are required to bind Caln with high affinity and that inhibit Caln activity with a potency similar to that of full-length RCAN1 (37). The highly conserved FLISPPXSPP sequence motif is apparently not critical for Caln binding and inhibition, as shown by mutants of RCAN1 with amino acid substitutions within the conserved motif (37, 42), although there is controversy as shown below. Consistent with these reports, we observed that Dyrk1A-mediated phosphorylation of RCAN1 at Thr192 enhanced its binding to Caln (Fig. 5, A and B), and there was little difference between RCAN1(S112A) mutant and RCAN1 WT in terms of their effect on Caln binding and activity.
A yeast model of Down syndrome
2007, International Journal of Developmental NeuroscienceCitation Excerpt :In recent years, intracellular interactions have been demonstrated between two genes on HSA21, DSCR1 and Dyrk1a (Chang and Min, 2005; Harris et al., 2005). The interaction of these genes on transcription factors can impact on the secondary gene dosage effect in ways previously unconsidered (de la Luna and Estivill, 2006). How many more HSA21 genes that interact is unknown.
Mental retardation in Down syndrome: From gene dosage imbalance to molecular and cellular mechanisms
2007, Neuroscience ResearchDown syndrome gene dosage imbalance on cerebellum development
2007, Progress in Neurobiology