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Hum Mol Genet. 2014 Dec 20;23(25):6746-61. doi: 10.1093/hmg/ddu392. Epub 2014 Jul 30.

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

Author information

  • 1Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano 20133, Italy.
  • 2Center Hemostasis and Thrombosis, Hematology Section, Department of Medical Sciences, University of Ferrara, Ferrara 44124, Italy.
  • 3Unit of Neurological Genetics, Department of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy.
  • 4SCDU Neurology, AOU "Maggiore della Carità", Novara 28100, Italy Interdisciplinary Research Center of Autoimmune Diseases IRCAD and.
  • 5Department of Neurosciences, University Hospital, Verona 37134, Italy.
  • 6Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
  • 7Department of Neurology, Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Brigham & Women's Hospital, Boston, MA, USA Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA and Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 8Interdisciplinary Research Center of Autoimmune Diseases IRCAD and Department of Health Sciences, University of Eastern Piedmont, Novara 28100, Italy.
  • 9Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano 20133, Italy rosanna.asselta@unimi.it rosanna.asselta@gmail.com.

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.

PMID:
25080502
DOI:
10.1093/hmg/ddu392
[PubMed - indexed for MEDLINE]
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