Down syndrome critical region gene 1, also known as DSCR1, is a protein that in humans is encoded by the ''RCAN1'' gene.

Gene location and organization

DSCR1 in human is located at the

centromeric The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers ...

border of the DSCR and encodes an inhibitor of calcineurin/ NFAT (nuclear factor activated T cells) signalling. DSCR1 genomic sequence of total 45 kb contain 7

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

and 6 introns , different

cDNA In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a speci ...

analysis yield first four exons are alternative and code for two isoforms of 197 amino acids, and one isoform code for 171 amino acids which differ in their N terminal . While the rest of the 168 residues are common. There is also alternative promoter region with about 900 bp between exon 3 and 4 suggesting that the fourth isoform might be penetrated from another promoter.

Function

The protein encoded by this gene interacts with calcineurin A and inhibits calcineurin-dependent signaling pathways of genetic transcription, possibly affecting central nervous system development. Three transcript variants encoding three different isoforms have been found for this gene. In endothelial cells, VEGF stimulates RCAN1.4 expression which regulates gene expression, cell migration and tubular morphogenesis.

Structure

DSCR1 Consist of putative functional motifs and calcineurin binding domain. DSCR1 contains two proline-rich SH3 binding domain, usually named proline-rich domain (PRD), which defines the protein family. SH3 domains or PRD are very important to allow the binding of the protein to endocytosis-related proteins such as ITSN1 and amphiphysin 1 and 2.

Clinical significance

This gene is located in the minimal candidate region for the Down syndrome phenotype, and is overexpressed in the brain of Down syndrome fetuses. Chronic overexpression of this gene may lead to neurofibrillary tangles such as those associated with

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

. RCAN1 helps coordinate whole-body metabolism and can be an important target in treatment of obesity.

Associated diseases

Central nervous system

All Down syndrome (DS) patients develop neuropathological changes identical to the pathogenesis of

(AD) in middle age, such as neuritic plaques and neuronal loss. Therefore, DS patients are perfect models to study AD pathogenesis. Chronic DSCR1 overexpression is related with DS and AD, while its shortage is reported in Huntington’s disease. DSCR1 expressed excessively in the Central Nervous System of embryos, and the protein is later overexpressed in brains of DS patients. However, neurotrophic peptide PACAP (or Pituitary adenylate cyclase-activating peptide) which is responsible for the development, differentiation, and survival, and various parts of memory and learning, targets RCAN1, a Down syndrome related gene, induces the expression of regulator of calcineurin 1, through activation of the PKA-CREB pathway, and this is important to understand the mechanisms of neural differentiation and aim for proper expression of RCAN1.

Cancer

It is suggested that the reason patients with Down syndrome are less predisposed to certain cancers is due to the impact of this gene of reducing blood supply to tumour cells. It is also proposed by epidemiological studies that DS patients are in greater risk of leukaemia, on the other hand they are at lower risk of cancer and other

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

related diseases such as diabetic retinopathy and atherosclerosis, indicating that one or more trisomic genes on chromosome 21 is responsible for protecting DS patients against cancer, and this cancer defence could be a result of angiogenesis suppression.

Interactions

DSCR1 has been shown to interact with Calcineurin. Hydrogen peroxide (H₂O₂) increases the overexpression of protein RCAN1. However, anti-oxidants and inhibitors of mitogen-activated protein kinases (MAPK) treatment block the increased expression of RCAN1 by H₂O₂. Demonstrating that the increased expression is a result of generating reactive oxygen species and activation of MAPK. Furthermore, phosphorylation is important to regulator RCAN1 protein expression. Because phosphorylation of RCAN1 expression by H₂O₂ increases of the half-life of the protein.