Both ISRE and GAS Interferon regulatory sequences found in chromosome 21 genes that are important in brain development and function. A. Jagadeesh, J. Nagappa, K. Sampson, H. North, L. Gutman, P. Lenferna de la Motte, M. Sellers, I. Dhanoya, D. Elyaman, J. Husni, L. E. Maroun Microbiology and Immunology, St.Matthew's University School of Medicine, Grand Cayman, Cayman islands.
The interferons can cause neuropathology.The cells from a person with trisomy 21 (T21)(Down syndrome(DS))would be expected to show a 50%increase in sensitivity to interferon (IFN) based on the presence on Ch21 of 3 of the 4 main interferon receptor component genes.The expected presence of a 50%increase in IFN receptors on T21 cells has been demonstrated.However,T21 cells are excessively sensitive to IFN action in the range of 5 to 10 fold greater than their euploid counterparts.We test our hypothesis that this greater-than-expected sensitivity could be due to the presence on Ch21 of genes that are a target for IFN up regulation by using online search engines to search for IFN regulatory sequences in or close to Ch21 genes.The control site for IFN-alpha regulated genes is termed the ISRE (Interferon Stimulated Response Element). The comparable site for IFN-gamma regulated genes is termed the GAS(Gamma Activated Sequence).Our strict criteria for labeling a gene as potentially interferon regulated required contiguous homology to at least 11 of 13 or 12 of 15 bases of a known ISRE,plus complete homology to at least one known GAS sequence, all located within the gene or, just upstream of the gene transcription start site. In addition,we consider here only genes potentially involved in brain development, function or dysfunction.To date,the following four genes have been found that meet these stringent criteria (based on homology with documented ISRE/GAS sequences):DOPEY2: The distribution of this protein during brain development has led to the suggestion that it plays a role in DS.Sites found:ISRE:FactorB,HLA-A,GAS:FCGR1,ICAM-1.SIM2:SIM2is a transcription factor found in the brain regions altered in DS.Sites found:ISRE:MX1,GAS:c-fos67[in tandem with ICAM-1].PCBP3:PCBP3 is a splicing factor that can alter the mRNA for Tau,a suspect gene in DS. Sites found:ISRE:BF,HLA-A(present twice),Factor B, GAS:ICAM-1.RCAN1:RCAN1 is a regulator of calcineurin.Its aberrant expression is associated with altered neuronal vesicular trafficking.Sites found:ISRE:ISG20,GIP3,IFITM3,GAS:IRF-1.There has been no previous indication in the literature that these genes are IFN regulated. They join a group of genes on Ch21 already shown to be IFN regulated (NCAM2, mir155, MX, and CD18).Together,these genes support the possibility that the super-sensitivity of Ch21 cells to the IFNs may be due to the presence on Ch21 of both IFN receptor genes and genes that are a target of IFN action.
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