Abstract
Down syndrome (DS), also known as trisomy 21 (T21), is associated with interferon (IFN) hypersensitivity, as well as predilections for Alzheimer's dementia (AD) and various autoimmune diseases. IFN-α and IFN-γ receptors are encoded on chromosome 21 (Ch21). It remains unclear how other Ch21 genes contribute to the neuropathological features of DS/T21. This study tests the hypothesis that identifying IFN-stimulated response element (ISRE) control sites on Ch21 will mark novel candidate genes for DS/T21-related IFN hypersensitivity and neuropathology not previously reported to be associated with IFN functions. We performed whole chromosome searches of online databases. The general ISRE consensus and gamma interferon activation consensus sequences (GAS) were used for identifying IFN-stimulated response elements. Candidate genes were defined as those possessing two or more ISRE and/or GAS control sites within and/or upstream of the transcription start site. A literature search of gene functions was used to select the candidate genes most likely to explain neuropathology associated with IFN hypersensitivity. DOPEY2, TMEM50B, PCBP3, RCAN1, and SIM2 were found to meet the aforementioned gene search and functional criteria. These findings suggest that DOPEY2, TMEM50B, PCBP3, RCAN1, and SIM2 are genes which may be dysregulated in DS/T21 and may therefore serve as novel targets for treatments aimed at ameliorating the neuropathological features of DS/T21. Future studies should determine whether these genes are dysregulated in patients with DS, DS-related AD, and autoimmune diseases.
Highlights
Trisomy 21 (T21) causes a variety of phenotypes known as Down syndrome (DS)
We found four consensus sequences in close proximity to the transcription start site. e complete control site reported for the gene encoding for the protein known as high affinity immunoglobulin gamma Fc receptor-1 (FCGR1) is located inside the gene 2009 base pairs downstream from the transcription start site followed by the control site for the gene encoding for intercellular adhesion molecule-1 (ICAM1) separated by 1533 base pairs. e gene for complement factor B and human leukocyte antigen-A (Factor B, HLA-AI) control sites are located upstream to the transcription start site
Discussion e main findings of this study are that DOPEY2, TMEM50B, PCBP3, RCAN1, and SIM2 contain at least two IFN-α stimulated response element (ISRE) sequences and one GAS control site upstream of their transcription start sites on Ch21, which qualifies them as IFN-regulated genes. e genes identified in this in silico analysis are potentially induced by type1 and/or type2 IFNs; future experimental studies will be needed to confirm this prediction
Summary
Autoimmune Mechanisms of Interferon Hypersensitivity and Neurodegenerative Diseases: Down Syndrome. Down syndrome (DS), known as trisomy 21 (T21), is associated with interferon (IFN) hypersensitivity, as well as predilections for Alzheimer’s dementia (AD) and various autoimmune diseases. IFN-α and IFN-c receptors are encoded on chromosome 21 (Ch21) It remains unclear how other Ch21 genes contribute to the neuropathological features of DS/T21. Is study tests the hypothesis that identifying IFN-stimulated response element (ISRE) control sites on Ch21 will mark novel candidate genes for DS/ T21-related IFN hypersensitivity and neuropathology not previously reported to be associated with IFN functions. A literature search of gene functions was used to select the candidate genes most likely to explain neuropathology associated with IFN hypersensitivity. Ese findings suggest that DOPEY2, TMEM50B, PCBP3, RCAN1, and SIM2 are genes which may be dysregulated in DS/T21 and may serve as novel targets for treatments aimed at ameliorating the neuropathological features of DS/T21. Future studies should determine whether these genes are dysregulated in patients with DS, DS-related AD, and autoimmune diseases
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