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Hum Mol Genet DOI:10.1093/hmg/ddu392

Functional variations modulating PRKCA expression and alternative splicing predispose to multiple sclerosis.

Publication TypeJournal Article
Year of Publication2014
AuthorsParaboschi, EM, Rimoldi, V, Soldà, G, Tabaglio, T, Dall'Osso, C, Saba, E, Vigliano, M, Salviati, A, Leone, M, Benedetti, MD, Fornasari, D, Saarela, J, De Jager, PL, Patsopoulos, NA, D'Alfonso, S, Gemmati, D, Duga, S, Asselta, R
JournalHum Mol Genet
Volume23
Issue25
Pages6746-61
Date Published2014 Dec 20
ISSN1460-2083
KeywordsAlleles, Alternative Splicing, Cell Line, Chromosomes, Human, Pair 17, Exons, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, INDEL Mutation, Introns, Male, Middle Aged, Multiple Sclerosis, Promoter Regions, Genetic, Protein Kinase C-alpha, RNA Stability, RNA, Messenger, Signal Transduction
Abstract

The protein kinase C alpha (PRKCA) gene, encoding a Th17-cell-selective kinase, was repeatedly associated with multiple sclerosis (MS), but the underlying pathogenic mechanism remains unknown. We replicated the association in Italians (409 cases, 723 controls), identifying a protective signal in the PRKCA promoter (P = 0.033), and a risk haplotype in intron 3 (P = 7.7 × 10(-4); meta-analysis with previously published data: P = 4.01 × 10(-8)). Expression experiments demonstrated that the protective signal is associated with alleles conferring higher PRKCA expression levels, well fitting our observation that MS patients have significantly lower PRKCA mRNA levels in blood. The risk haplotype was shown to be driven by a GGTG ins/del polymorphism influencing the heterogeneous nuclear ribonucleoprotein H-dependent inclusion/skipping of a PRKCA alternative exon 3*. Indeed, exon 3* can be present in two different versions in PRKCA mRNAs (out-of-frame 61 bp or in-frame 66 bp long), and is preferentially included in transcripts generated through a premature polyadenylation event. The GGTG insertion downregulates 3* inclusion and shifts splicing towards the 66 bp isoform. Both events reduce the nonsense-mediated mRNA-decay-induced degradation of exon 3*-containing mRNAs. Since we demonstrated that the protein isoform produced through premature polyadenylation aberrantly localizes to the plasma membrane and/or in cytoplasmic clusters, dysregulated PRKCA 3* inclusion may represent an additional mechanism relevant to MS susceptibility.

URLhttp://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=25080502
DOI10.1093/hmg/ddu392
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25080502?dopt=Abstract

Alternate JournalHum. Mol. Genet.
PubMed ID25080502