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Critical Genes in Down Syndrome« Back to Volume 22, Issue 4, December 2006 - Table of Contents One of the most common birth defect syndromes in humans, Down syndrome (DS), is caused by the presence of an extra copy of a major portion (containing about 200-300 genes) of chromosome 21. The chromosomal region has been called the DS critical region (DSCR). Many, if not most, experts would agree that the DS clinical phenotype results from the 1.5-fold increase in expression of some, perhaps most, or even all of these genes. Arron et al reported a mechanism through which increased dosage of 2 genes from this region may lead to many of the features of DS. The initial observation was serendipitous coming from experiments addressing the developmental interplay between the enzyme calcineurin and a family of 4 gene regulatory factors termed NFATc (nuclear-factor of activated T cells). The transcriptional functions of NFATc members are regulated in part by phosphorylation and its effect on nuclear import and export. The NFATc phosphorylation promotes nuclear export to the cytoplasm where the transcription factors are inactive; in contrast, functional NFATc proteins residing in the nucleus are dephosphorylated. As illustrated in the figure, this regulatory scheme is controlled by entry of calcium into the cell. Calcium influx leads to calcineurin-mediated NFATc dephosphorylation, nuclear entry, and activation of NFATc target genes. Getting back to the DS story, the authors noted a striking similarity in phenotype between human DS and mice in whom components of the NFATc signaling pathway had been genetically inactivated. They validated this observation by documenting a number of anatomic, physiologic, and even behavioral similarities between mice showing abnormal NFATc function and human DS, as well as several accepted mouse models of human DS. With phenotypic similarity confirmed, the researchers sought genes residing within the human DSCR whose functions might reduce NFATc transcriptional activity. Two candidate loci were identified: DSCR1 (Down syndrome critical region gene 1, alternatively termed myocyte-enriched calcineurin-interacting protein 1) and DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A). DSCR1 encodes an inhibitor of calcineurin/NFAT signaling; it is known to be expressed at higher levels in DS fetuses. The DYRK1A encodes a nuclear serine/threonine kinase that primes substrates for phosphorylation by GSK3 (Glycogen synthetase kinase 3); GSK3-mediated phosphorylation of NFATc proteins in the nucleus leads to their inactivation and export. NFAT signaling and Down syndrome. Calcium signaling through the NFATc pathway mediates many developmental processes and the immune response. Reprinted with permission from: Epstein CJ. Nature, 2006;441:582–583. Copyright © NPG. 2006 All rights reserved. To determine if increasing the dosage of DSCR1 and DYRK1A can reproduce features of human DS, several lines of transgenic mice were engineered to overexpress the 2 genes. The authors mainly monitored heart development. Overexpression of DYRK1A at a level 2–3 fold above endogenous levels was sufficient to induce heart defects and block heart development. They also observed decreased expression of NFATc target genes consistent with their proposed model. Expression of both DSCR1 and DYRK1A to 1.5- to 2-fold above endogenous levels lead to heart defects similar to those detected in the NFATc knock-out mice that had spawned to investigations, and these developmental abnormalities were associated with inactivated NFATc1 judged from its hyperphosphorylation and cytoplasmic location. From modeling the NFAT genetic regulatory circuit, the authors suggested that the DSCR1 and DYRK1A proteins have additive effects. They further propose that activating promoters of target genes requires a threshold level of NFAT complexes below which these genes may fail to be transcribed. They suggest that a 1.5-fold increase in DSCR1 and DYRK1A dosage may be sufficient to keep NFAT complexes below this level, at least at certain critical times in development. To test this concept, the authors examined tissues from 2 mouse models of DS, and from 3 human DS fetuses, and controls at 17-21 weeks gestation. Although the results were not completely clear, they supported the prediction. For instance, the investigators detected increased DYRK1A expression and excessive NFATc4 phosphorylation in cortical neurons of late stage embryos in one DS mouse strain. Similarly, they observed hyperphosphorylated NFATc4 and NFATc1 in the brain and heart, respectively, of one of the human fetuses. The authors concluded that perturbations of the NFATc genetic regulatory circuit due to increased dosage for DSCR1 and DYRK1A may explain many of the developmental abnormalities of human DS. Editor’s CommentThis paper, combined with the editorial by Epstein,1 provide novel insights into molecular mechanisms that may contribute to the clinical phenotype of DS. Both point out the difficulties in proving this concept, given significant differences between human and mouse development and between human DS and the mouse models of DS that do not precisely match the trisomic state in humans. Nevertheless, the findings provide food for thought for countering a possible genetic regulatory disturbance, keeping in mind the extreme complexity of the challenge. William A. Horton, MD
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Volume 25 Number 1
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