A Functional SNP Catalog of Overlapping miRNA-Binding Sites in Genes Implicated in Prion Disease and Other Neurodegenerative Disorders

• Published in: Human mutation Vol. 35; no. 10; pp. 1233 - 1248
• Main Authors: Saba, Reuben, Medina, Sarah J., Booth, Stephanie A.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.10.2014; Hindawi Limited
• Subjects: 3' Untranslated Regions; 3′-UTR; Animals; Binding sites; Binding Sites - genetics; CA1 Region, Hippocampal - metabolism; CNS; Computer Simulation; Databases, Nucleic Acid; GABA-receptors; Gene Expression Regulation; Genes; Humans; Mice; MicroRNAs; miRNAs; Mutation; neurodegeneration; Neurodegenerative Diseases - genetics; Neurological disorders; Neurons - metabolism; Polymorphism, Single Nucleotide; Prion disease; Prion Diseases - genetics; Prions; Receptors, GABA - genetics; SNPs; GABA-receptors; Prion disease; miRNAs; 3′-UTR; SNPs; neurodegeneration; CNS
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22627

ABSTRACT The involvement of SNPs in miRNA target sites remains poorly investigated in neurodegenerative disease. In addition to associations with disease risk, such genetic variations can also provide novel insight into mechanistic pathways that may be responsible for disease etiology and/or pathobiology. To identify SNPs associated specifically with degenerating neurons, we restricted our analysis to genes that are dysregulated in CA1 hippocampal neurons of mice during early, preclinical phase of Prion disease. The 125 genes chosen are also implicated in other numerous degenerative and neurological diseases and disorders and are therefore likely to be of fundamental importance. We predicted those SNPs that could increase, decrease, or have neutral effects on miRNA binding. This group of genes was more likely to possess DNA variants than were genes chosen at random. Furthermore, many of the SNPs are common within the human population, and could contribute to the growing awareness that miRNAs and associated SNPs could account for detrimental neurological states. Interestingly, SNPs that overlapped miRNA‐binding sites in the 3′‐UTR of GABA‐receptor subunit coding genes were particularly enriched. Moreover, we demonstrated that SNP rs9291296 would strengthen miR‐26a‐5p binding to a highly conserved site in the 3′‐UTR of gamma‐aminobutyric acid receptor subunit alpha‐4. We identified numerous SNPs overlapping miRNA‐binding sites within an assortment of genes implicated in the very early mechanisms of neurodegeneration characterized by Prion disease. Many of these SNPs are functional as they alter the binding potential of spatiotemporally coexpressed miRNAs. Additionally, we also show that these SNPs are common within the human population. Taken together, our data contribute to the emerging awareness that miRNAs and associated SNPs could account for detrimental neurological states that afflict humans.