title: Susceptibility variants in the CD58 gene locus point to a role of microRNA-548ac in the pathogenesis of multiple sclerosis.
abstract: Multiple sclerosis (MS) is a neurological immune-driven disease of unknown etiology. A genetic contribution to MS susceptibility is well established and more than 100 associated genomic regions have been identified. However, there is little understanding of how individual genetic variants are involved in the pathogenesis of MS. Single nucleotide polymorphisms (SNPs) within the first intron of CD58 have been independently confirmed to be related to the risk of MS. We here provide evidence that these SNPs may implicate an altered processing of an intronic microRNA. This microRNA, hsa-mir-548ac, belongs to a huge primate-specific family of microRNAs that evolved from a mariner-derived transposable element (Made1). Sequencing data of the 1000 Genomes project revealed a SNP, rs1414273, at the base of the microRNA stem-loop to be in strong linkage disequilibrium with the MS-associated haplotype. This SNP is suspected to affect the recognition of the primary microRNA hairpin by Drosha and its cofactor DGCR8. Future studies on microRNA-548ac and its genetic variant may yield deeper insights into the mechanisms underlying MS. Experimental challenges and open questions are discussed.
authors: University of Rostock, Department of Neurology, Division of Neuroimmunology, Gehlsheimer Str. 20, 18147 Rostock, Germany. Electronic address: michael.hecker@rocketmail.com.
authors: Michael
authors: M
authors: Hecker
authors: University of Rostock, Department of Neurology, Division of Neuroimmunology, Gehlsheimer Str. 20, 18147 Rostock, Germany. Electronic address: brit.fitzner@uni-rostock.de.
authors: Brit
authors: B
authors: Fitzner
authors: University of Rostock, Department of Neurology, Division of Neuroimmunology, Gehlsheimer Str. 20, 18147 Rostock, Germany. Electronic address: blaschke.jana@googlemail.com.
authors: Jana
authors: J
authors: Blaschke
authors: University of Rostock, Department of Neurology, Division of Neuroimmunology, Gehlsheimer Str. 20, 18147 Rostock, Germany. Electronic address: paul.blaschke@uni-rostock.de.
authors: Paul
authors: P
authors: Blaschke
authors: University of Rostock, Department of Neurology, Division of Neuroimmunology, Gehlsheimer Str. 20, 18147 Rostock, Germany. Electronic address: uwe.zettl@med.uni-rostock.de.
authors: Uwe Klaus
authors: UK
authors: Zettl
mesh_terms: D000818:Animals; D018968:CD58 Antigens / Q000235:genetics*; D004251:DNA Transposable Elements; D019143:Evolution, Molecular; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011323:Primates / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism
chemical_list: D018968:CD58 Antigens; C474043:DGCR8 protein, human; D004251:DNA Transposable Elements; C561887:MIRN548 microRNA, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C517918:DROSHA protein, human; D043244:Ribonuclease III
keywords: Genetic risk; Multiple sclerosis; Single nucleotide polymorphisms; Transposable element; microRNA