title: A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome.
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.
authors.affiliation: Department of Neurology, alessandro.didonna@ucsf.edu.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Didonna
authors.affiliation: Department of Neurology.
authors.forename: Noriko
authors.initials: N
authors.lastname: Isobe
authors.affiliation: Department of Neurology.
authors.forename: Stacy J
authors.initials: SJ
authors.lastname: Caillier
authors.affiliation: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Kathy H
authors.initials: KH
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Alma L
authors.initials: AL
authors.lastname: Burlingame
authors.affiliation: Department of Neurology.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.affiliation: Department of Neurology.
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.affiliation: 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.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.affiliation: Department of Neurology.
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
mesh_terms: D018797:Cell Cycle Proteins; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D020690:GTPase-Activating Proteins; D006367:HeLa Cells; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020543:Proteome / Q000378:metabolism; D012307:Risk Factors
chemical_list: D018797:Cell Cycle Proteins; C506399:EVI5 protein, human; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; D020543:Proteome