A Non-synonymous Single-nucleotide Polymorphism Associated with Multiple Sclerosis Risk Affects the EVI5 Interactome

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2015 Oct 5

PMID 26433934

Citations 9

Authors

Alessandro Didonna

Noriko Isobe

Stacy J Caillier

Kathy H Li

Alma L Burlingame

Stephen L Hauser

Sergio E Baranzini

Nikolaos A Patsopoulos

Jorge R Oksenberg

Affiliations

Soon will be listed here.

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.

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