Susceptibility variants in the CD58 gene locus point to a role of microRNA-548ac in the pathogenesis of multiple sclerosis

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.

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