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

Elvezia M. Paraboschi, Valeria Rimoldi, Giulia Soldà, Tommaso Tabaglio, Claudia Dall'Osso, Elena Saba, Marco Vigliano, Alessandro Salviati, Maurizio Leone, Maria D. Benedetti, Diego Fornasari, Janna Saarela, Philip L. De Jager, Nikolaos A. Patsopoulos, Sandra D'Alfonso, Donato Gemmati, Stefano Duga, Rosanna Asselta

Research output: Contribution to journalArticle

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 haplotypewas 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 plasmamembrane and/or in cytoplasmic clusters, dysregulated PRKCA 3* inclusion may represent an additional mechanism relevant to MS susceptibility.

Original languageEnglish
Pages (from-to)6746-6761
Number of pages16
JournalHuman Molecular Genetics
Volume23
Issue number25
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology
  • Medicine(all)

Fingerprint Dive into the research topics of 'Functional variations modulating PRKCA expression and alternative splicing predispose to multiple sclerosis'. Together they form a unique fingerprint.

  • Cite this

    Paraboschi, E. M., Rimoldi, V., Soldà, G., Tabaglio, T., Dall'Osso, C., Saba, E., Vigliano, M., Salviati, A., Leone, M., Benedetti, M. D., Fornasari, D., Saarela, J., De Jager, P. L., Patsopoulos, N. A., D'Alfonso, S., Gemmati, D., Duga, S., & Asselta, R. (2014). Functional variations modulating PRKCA expression and alternative splicing predispose to multiple sclerosis. Human Molecular Genetics, 23(25), 6746-6761. https://doi.org/10.1093/hmg/ddu392