1. Functional variations modulating PRKCA expression and alternative splicing predispose to multiple sclerosis.
- Author
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Paraboschi 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, and Asselta R
- Subjects
- Alleles, Cell Line, Chromosomes, Human, Pair 17 chemistry, Exons, Female, Genetic Loci, Humans, INDEL Mutation, Introns, Male, Middle Aged, Multiple Sclerosis metabolism, Multiple Sclerosis pathology, Promoter Regions, Genetic, Protein Kinase C-alpha chemistry, Protein Kinase C-alpha metabolism, RNA Stability, RNA, Messenger chemistry, RNA, Messenger metabolism, Signal Transduction, Alternative Splicing, Genetic Predisposition to Disease, Multiple Sclerosis genetics, Protein Kinase C-alpha genetics, RNA, Messenger genetics
- 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., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2014
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