Genomic Organization, Alternative Splicing, and Expression Patterns of theDSCR1(Down Syndrome Candidate Region 1) Gene
ABSTRACT Down syndrome is a major cause of mental retardation and congenital heart defects and is due to the presence of three copies of human chromosome 21 in the affected individual. We have identified a gene, DSCR1 (HGMW-approved symbol), from the region 21q22.1-q22.2, which is highly expressed in human fetal brain and adult heart. Structural features of the conceptual protein encourage us to propose involvement of DSCR1 in the regulation of transcription and/or signal transduction. Higher expression of RNA in the brains of young rats compared to adults suggests a possible role for the gene in the development of the central nervous system. We have determined the genomic organization of DSCR1 and identified three additional alternative first exons by RACE and cDNA library screening. DSCR1 spans nearly 45 kb of genomic DNA and comprises seven exons, four of which (exons 1-4) are alternative first exons. All the exons are flanked by splice junctions that conform to the consensus AG-GT motif. We have studied the expression patterns of the alternative first exons. Exon 2 was detected in fetal brain and liver by RT-PCR. Both exons 1 and 4 were differentially expressed in fetal brain, lung, liver, and kidney and in all adult tissues tested by Northern analysis with two notable exceptions: exon 1 was not detected in adult kidney and exon 4 was not found in adult brain. The high level of expression of exon 1 in fetal brain suggests that this alternative form of DSCR1 has an important role in brain development. This information should help us to understand the possible relationship of DSCR1 with Down syndrome and aid in the development of animal models.
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ABSTRACT: Atherosclerosis is a complex inflammatory disease involving extensive vascular vessel remodelling and migration of vascular cells. As RCAN1 is implicated in cell migration, we investigated its contribution to atherosclerosis. We show RCAN1 induction in atherosclerotic human and mouse tissues. Rcan1 was expressed in lesional macrophages, endothelial cells and vascular smooth muscle cells and was induced by treatment of these cells with oxidized LDLs (oxLDLs). Rcan1 regulates CD36 expression and its genetic inactivation reduced atherosclerosis extension and severity in Apoe(-/-) mice. This effect was mechanistically linked to diminished oxLDL uptake, resistance to oxLDL-mediated inhibition of macrophage migration and increased lesional IL-10 and mannose receptor expression. Moreover, Apoe(-/-) Rcan1(-/-) macrophages expressed higher-than-Apoe(-/-) levels of anti-inflammatory markers. We previously showed that Rcan1 mediates aneurysm development and that its expression is not required in haematopoietic cells for this process. However, transplantation of Apoe(-/-) Rcan1(-/-) bone-marrow (BM) cells into Apoe(-/-) recipients confers atherosclerosis resistance. Our data define a major role for haematopoietic Rcan1 in atherosclerosis and suggest that therapies aimed at inhibiting RCAN1 expression or function might significantly reduce atherosclerosis burden.EMBO Molecular Medicine 12/2013; 5(12). DOI:10.1002/emmm.201302842 · 8.25 Impact Factor
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ABSTRACT: The regulators of calcineurin (RCAN) proteins, previously known as calcipressins, have been considered to be a well conserved family from yeast to human based on the conservation of their FLISPP motif. Here, after performing a RCAN comparative genomic analysis we propose the existence of a novel functionally closely related RCAN subfamily restricted to vertebrates, the other RCAN proteins being considered only as distantly related members of the family. In addition, while three paralogous RCAN genes are found in vertebrates, there is only one in the other members of Eukarya. Moreover, besides the FLISPP motif, these paralogous genes have two others conserved motifs, the Cn-inhibitor RCAN (CIC) and the PxIxxT, which are restricted to vertebrates. In humans, RCAN1 and RCAN2 bind and inhibit Cn through their C-terminal region. Given the high amino acid identity in this region among human RCANs, authors in the field have hypothesized a role for RCAN3 in inhibiting Cn activity. Here, we demonstrate for the first time that human RCAN3, encoded by the RCAN3 (also known as DSCR1L2) gene, interacts physically and functionally with Cn. This interaction takes place only through the RCAN3 CIC motif. Overexpression of this sequence inhibits Cn activity towards the nuclear factor of activated T cells (NFAT) transcription factors and down-regulates NFAT-dependent cytokine gene expression in activated human Jurkat T cells.Biochimica et Biophysica Acta 04/2007; 1773(3):330-41. DOI:10.1016/j.bbamcr.2006.12.007 · 4.66 Impact Factor
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ABSTRACT: The Down syndrome critical region 1 (DSCR1) gene is located in syntenic regions of human chromosome 21 and mouse chromosome 16 and encodes a regulatory protein in the calcineurin/NFAT pathway. DSCR1 expression in the embryonic brain, craniofacial structures, and heart is consistent with a role in contributing to Down syndrome developmental anomalies. In the trisomy 16 (Ts16) murine model of Down syndrome, expression of DSCR1 isoforms is elevated and NFAT transcriptional activity is decreased in the developing heart and brain. The individual contribution of DSCR1 to Down syndrome-related anomalies was examined by specific restoration of DSCR1 to disomic levels in Ts16 embryos. However, genetic restoration of DSCR1 did not rescue major morphological abnormalities in cardiac or craniofacial development. These data demonstrate that trisomy of DSCR1 alone does not significantly contribute to developmental defects in Ts16 mice and underscore the complexity of developmental anomalies associated with Down syndrome.Developmental Dynamics 07/2005; 233(3):954-63. DOI:10.1002/dvdy.20433 · 2.67 Impact Factor