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Hum Mol Genet. 2015 Dec 15;24(24):7151-8. doi: 10.1093/hmg/ddv412. Epub 2015 Oct 3.

A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome.

Author information

1
Department of Neurology, alessandro.didonna@ucsf.edu.
2
Department of Neurology.
3
Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Institute for the Neurosciences and Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02142, USA.

Abstract

Despite recent progress in the characterization of genetic loci associated with multiple sclerosis (MS) risk, the ubiquitous linkage disequilibrium operating across the genome has stalled efforts to distinguish causative variants from proxy single-nucleotide polymorphisms (SNPs). Here, we have identified through fine mapping and meta-analysis EVI5 as the most plausible disease risk gene within the 1p22.1 locus. We further show that an exonic SNP associated with risk induces changes in superficial hydrophobicity patterns of the coiled-coil domain of EVI5, which, in turns, affects the EVI5 interactome. Immunoprecipitation of wild-type and mutated EVI5 followed by mass spectrometry generated a roster of disease-specific interactors functionally linked to lipid metabolism. Among the exclusive binding partners of the risk variant, we describe the novel interaction with sphingosine 1-phosphate lyase (SGPL1)-a key enzyme for the creation of the sphingosine-1 phosphate gradient, which is relevant to the pathogenic process and therapeutic management of MS.

PMID:
26433934
PMCID:
PMC5007634
DOI:
10.1093/hmg/ddv412
[Indexed for MEDLINE]
Free PMC Article

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