Trisomy 21 is the most common familial cause of mental deceleration and one of the few aneuploidies compatible with post-natal endurance. It occurs in 1 out of 700 unrecorded births in all cultural groups. The huge bulk of meiotic mistakes taking to the trisomic status occur in the egg, as about 90 % of instances involve an extra maternal chromosome ( 1 ) . Besides mental deceleration, present in every person with Down syndrome, trisomy 21 is associated with more than 80 clinical traits including inborn bosom disease, duodenal stricture or atresia, imperforate anus, Hirschprung disease, musculus hypotonus, immune system lacks, increased hazard of childhood leukemia and early oncoming Alzheimer ‘s disease ( 1 ) . The Human Down Syndrome Critical Region 1 cistron is located on chromosome 21 in the part of 21q22.12. This cistron is involved in cellular version to oxidative emphasis, transiently protecting cells that have been primed with a low dosage of an oxidant emphasis against subsequent, potentially deadly, challenges. It has been shown to be involved in Alzheimer ‘s disease every bit good as the bar of musculus hypertrophy and is likely to be involved in several disease tracts ( 2 ) . The DSCR1 cistron, besides referred to as Adapt 78 and MCIP1, is known to adhere and modulate calcineurin. It has been found to be expressed in diverse cell types and tissues, including heart/cardiac musculus, striated musculus, brain/neuronal cells, and T-cells, and plays an of import function in calcineurin ordinance in these cell types ( 3 ) . This cistron, encodes a protein that binds to and suppress the catalytic fractional monetary unit of calcineurin.
Figure 1. Chromosome 21: DSCR1 ( Adapt78 ) is located on chromosome 21 in the part q22.12. This lies outside of the Down Syndrome Candidate Region ( DSCR ) . DSCR1 Genomic Deoxyribonucleic acid: DSCR1 consists of seven coding DNAs separated by six noncoding DNAs that are instead spliced and vary in their 5 ‘ coding DNA, but all contain coding DNAs 5, 6 and 7. There is a bunch of 15 NFAT binding
sites on the DSCR1 cistron ( 2 ) .
Calcineurin/NFAT Signalling Pathway
The atomic factor of activated T-cells ( NFAT ) household of written text factors was originally identified in lymph cells for its function in cytokine cistron look. Beyond the immune system, NFAT proteins are expressed in many cell types including cardiac, skeletal, and vascular smooth musculus ( 4 ) . NFAT proteins are downstream effecters in the calcineurin signalling pathway-a critical tract in the transduction of many extracellular, adaptative stimulation. Calcineurin is a calcium-dependent, serine/threonine protein phosphatase that dephosphorylates NFAT to enable atomic translocation and mark cistron written text ( 4 ) . Recently, it has been reported that the protein merchandises of DSCR1, calcipressin 1s, are able to adhere to and suppress the catalytic fractional monetary unit of calcineurin ( protein phosphatase 2B ) . Calcineurin is under the control of calcium/calmodulin, it is a heterodimer, which consists of a catalytic fractional monetary unit, calcineurin A, and a regulative fractional monetary unit, calcineurin B ( 2 ) . Since DSCR1 proteins have been discovered to be endogenous inhibitors of calcineurin, they have been dubbed calcipressins. which has several known substrates – of these, the best characterized is the written text factor NFAT.
Fig. 2. Calcineurin fractional monetary units and NFAT isoforms in mouse, Drosophila, and C. elegans. Conserved protein spheres of calcineurin A, calcineurin B, and NFAT are presented. The regulative portion of calcineurin A includes calcineurin B and calmodulin interacting parts and an car inhibitory sphere. The four conserved EF-hand calcium-binding spheres ( C ) of calcineurin B are indicated. Within NFAT, the transactivation sphere ( TAD ) is located at the N-terminus, next to a regulative sphere incorporating sequences required for calcineurin binding, serine-rich motives, and atomic localisation signals. The conserved DNA binding sphere is of the rel homology category ( 5 ) .
Calcineurin signalling transduced by NFATs activation was first characterized in the immune system. Substrates of calcineurin phosphatase activity include most members of the NFAT household of written text factors ( 5 ) . Loss of specific NFAT isoforms consequences in cardiovascular, skeletal musculus, gristle, neural, or immune system defects. Calcineurin and NFATs have besides been implicated in the distinction of bone, gristle, musculus, tegument, and fat in tissue civilization experiments. Postnatally, this signalling tract contributes to normal homeostasis every bit good as pathological conditions in the tegument, cardiovascular system, skeletal musculus, immune cells, and cardinal nervous system ( 5 ) . These are many of the same organ systems that require calcineurin/NFAT signalling during embryologic development. Therefore, there is roll uping grounds for the widespread use of calcineurin/NFAT signalling mechanisms in a wide spectrum of developmental and disease procedures ( 5 ) . Calcineurin dephosphorylates NFATs in response to increased intracellular Ca and regulates cistron look in a assortment of calcium-sensitive tissues such as encephalon, musculus, and lymph cells. Transcriptional activity of NFATs is dependent on dephosphorylation by calcineurin, which leads to atomic translocation ( 5 ) . An extra degree of ordinance of calcineurin activity is through calcineurin interacting proteins including Down syndrome Critical Region 1. NFATs bind DNA with low affinity and normally move in concurrence with other written text factors such as AP-1, MEF2, or GATA4. Thus, the control of NFAT transcriptional regulative activity in association with other proteins likely represents a nodal point in crossing signal transduction tracts including calcineurin, MAPK, p38, JNK, and Wnt ( 5 ) . These include demands in nervous and muscular tissues that are among the organ systems affected in craniate embryos with altered calcineurin and NFAT signalling ( 5 ) .
Down Syndrome Critical Region Control on Organ and Vessel Development
Since DSCR1 has been confirmed to adhere to calcineurin catalytic A fractional monetary unit and act as a regulator of the calcineurin-mediated signalling tract, it was hypothesized that the up-regulation of DSCR1 cistron look in endothelial cells might move as an endogenous regulator of angiogenesis by modulating the calcineurin-NFAT signalling tract. Activation of calcineurin in endothelial cells by vascular cuticular growing factor ( 3 ) and calcium stimulators dephosphorylates NFATs, ensuing in NFAT translocation to the karyon where it activates written text of mark cistrons, including Cox-2, tissue factor, and isoform 4 of DSCR1. Newly synthesized DSCR1 protein so binds to and inhibits calcineurin. Therefore, DSCR1 synthesis serves as a negative feedback mechanism which dampens calcineurin activity and affects the look of the downstream response cistrons ( 3 ) . Surveies have demonstrated that the booster parts of DSCR1 isoform 4 cistrons contain multiple NFAT binding sites. These cistrons could hence be possible downstream marks of DSCR1. Over look of DSCR1 significantly down-regulates DSCR1 isoform 4 booster activity ( 3 ) . This repressive consequence correlated with the figure of NFAT adhering sites in the booster part: DSCR1 contains about 15 NFAT sites. Of peculiar importance, it should be noted that DSCR1 strongly regulates its ain booster activity via the calcineurin-NFAT signalling tract ( 3 ) . Since NFAT activity is of import for the activation of many pro-angiogenic cistrons, including Cox-2 and tissue factor, feedback suppression of NFAT by DSCR1 may stand for a of import molecular mechanism underlying the ordinance of angiogenic cistrons activated by the calcineurin-NFAT signalling tract in endothelial cells ( 3 ) . With over look of DSCR1 due to trisomy of chromosome 21, suppressing angiogenesis would do underdevelopment of vass and variety meats and so is possibly a factor that causes Down Syndrome characteristics.
Fig. 3. Hypothesized conventional profile of DSCR1 cistron look and its ordinance in response to VEGF intervention in endothelial cells ( 3 ) .
Down Syndrome Critical Region Control On Heart Development
Approximately 40-50 % of the lasting Down Syndrome patients have characteristic inborn bosom disease. Indeed, Down Syndrome is a major cause of inborn bosom defects in worlds. Endocardial shock absorber defect is the prevailing cardiac abnormalcy in Down Syndrome, taking to characteristic auriculoventricular septal or bosom valve lesions ( 6 ) . Previous work from research labs and others demonstrates that the calcineurin/NFAT signalling tract is indispensable for the development of endocardial shock absorbers and bosom valves, and that disturbances of the pathway lead to many characteristics of Down syndrome. Activation of this evolutionally conserved DSCR1 regulative sequence requires calcineurin and NFAT signalling in the endocardium ( 6 ) . NFAT proteins adhere to the regulative sequence and trigger its foil activity. NFAT is sufficient to bring on the look of DSCR1 in cells that usually have undetectable or minimum NFAT or DSCR1 ( 6 ) . Although recent work has shown that the look of DSCR1 in nerve cells and the bosom is induced by the NFAT tract, it is non clear how DSCR1 interacts with NFAT within the endocardium during bosom valve development. The function of calcineurin in modulating DSCR1 look in the bosom remains vague. Nor is at that place unambiguous grounds that DSCR1 is a direct transcriptional mark of NFAT in the bosom ( 6 ) . Besides the calcineurin/NFAT signalling tract besides plays a portion in vascular smooth musculus development, it has been shown to bring on vascular smooth musculus cell proliferation and migration in response to receptor tyrosine kinase ( RTK ) and G-protein-coupled receptor ( GPCR ) agonists, severally ( 9 ) . Barricading Calcineurin/NFAT signalling in vivo suppresses experimental balloon injury-induced neointimal hyperplasia, proposing Calcineurin/NFAT activity is involved in smooth musculus cell phenotypic transition. With over look of DSCR1 caused by triosomy of chromosome 21, this will barricade the calcineurin/NFAT signalling tract and so suppress vascular smooth musculus cells which in bend causes underdevelopment of the bosom ( 9 ) .
Down Syndrome Critical Region Control on Brain Development
The regulator of calcineurin proteins ( RCANs ) are a household of little, extremely conserved proteins that can adhere and suppress the calcium-regulated protein phosphatase calcineurin. Calcineurin is closely involved in many aspects of synaptic malleability and memory formation because of its ability to straight dephosphorylate critical marks in both the presynaptic and postsynaptic compartments of nerve cells. Calcineurin besides can indirectly advance dephosphorylation of many other proteins by increasing protein phosphatase 1 ( PP1 ) activity ( 7 ) . Calcineurin accomplishes this through dephosphorylation of the PP1 inhibitors inhibitor-1 ( I-1 ) and dopamine and cAMP-regulated phosphoprotein-32 ( DARPP-32 ) . Behavioural and electro physiological surveies utilizing both familial and pharmacological methods to change calcineurin activity indicate that calcineurin is likely a negative regulator of acquisition, memory, and synaptic malleability ( 7 ) . Finally, dysregulation of calcineurin activity is associated with many signifiers of encephalon disease and hurt, including Alzheimer ‘s disease and excitotoxic ischaemia. Because of the importance of calcineurin in modulating diverse neural procedures, there is turning involvement in the potency for trisomy of RCAN1, besides known as DSCR1 to lend to the overplus of phenotypes associated with Down syndrome through its interaction with calcineurin ( 7 ) . Therefore, understanding how RCAN1 contributes usually to mechanisms of acquisition and memory formation is critical to understanding its function in the shortages observed in Down syndrome and Alzheimer ‘s patients ( 7 ) .
Other Genes and Transcription Factors That Can Contribute to the Development of Down Syndrome
Even though calcineurin/NFAT signalling tract has a major function in the development of Down Syndrome phenotypes, there are besides other written text factors that are involved in the development of Down Syndrome. Prep1 belongs to the TALE category of homeodomain proteins and is indispensable for embryologic development ( 8 ) . Prep1 is a written text factor that, in combination with its major spouses, Pbx proteins, regulates the overall size of the being and single variety meats every bit good as major developmental tracts. PREP1 maps on chromosome 21 ( 21 ; q22.3 ) in worlds and chromosome 17 in mice and is over uttered 1.5-fold in encephalon tissues of Down Syndrome patients. The presence of PREP1 in the Down Syndrome Critical Region of chromosome 21 suggests that Prep1 might be involved in the phenotype of Down Syndrome ( 8 ) . With over look in encephalon tissue this could do patients with Down Syndrome the characteristic acquisition troubles. Another cistron is DYRK1 which is localized within the Down syndrome critical part ( DSCR ) of human chromosome 21, and with DSCR1 cistron synergistically cut down the atomic tenancy of the NFAT proteins. DYRK1 is a kinase that promotes NFAT atomic export. Apparently a 1.5-fold over look of these two proteins leads to the dysregulation of calcineurin/NFAT signalling, ensuing in a configuration of Down Syndrome characteristics ( 8 ) .
In decision Down Syndrome Critical Region has an of import function in the development of the characteristics and phenotype of Down Syndrome via the calcineurin/NFAT signalling pathway. This tract has been shown to be involved in the underdevelopment of variety meats peculiarly the bosom which contributes to the inborn bosom disease, which a big proportion of Down Syndrome patients suffer with and besides the encephalon where regulator of calcineurin proteins inhibit calcineurin and hence suppress the calcineurin/NFAT tract which prevents normal neural and encephalon development. With cognition on how characteristics of Down Syndrome are brought about by what cistrons, proteins and tracts, new drugs or therapies could be developed to either block these tracts, forestalling suppression ensuing in normal development, or by cistron omission so there is less look of Down Syndrome Critical Region Proteins.