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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)7151-7158
Number of pages8
JournalHuman Molecular Genetics
Volume24
Issue number24
DOIs
Publication statusPublished - Jan 1 2015
Externally publishedYes

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Multiple Sclerosis
Single Nucleotide Polymorphism
Genetic Loci
Linkage Disequilibrium
Proxy
Hydrophobic and Hydrophilic Interactions
Lipid Metabolism
Immunoprecipitation
Meta-Analysis
Mass Spectrometry
Genome
Enzymes
Genes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Didonna, A., Isobe, N., Caillier, S. J., Li, K. H., Burlingame, A. L., Hauser, S. L., ... Oksenberg, J. R. (2015). A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome. Human Molecular Genetics, 24(24), 7151-7158. https://doi.org/10.1093/hmg/ddv412

A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome. / Didonna, Alessandro; Isobe, Noriko; Caillier, Stacy J.; Li, Kathy H.; Burlingame, Alma L.; Hauser, Stephen L.; Baranzini, Sergio E.; Patsopoulos, Nikolaos A.; Oksenberg, Jorge R.

In: Human Molecular Genetics, Vol. 24, No. 24, 01.01.2015, p. 7151-7158.

Research output: Contribution to journalArticle

Didonna, A, Isobe, N, Caillier, SJ, Li, KH, Burlingame, AL, Hauser, SL, Baranzini, SE, Patsopoulos, NA & Oksenberg, JR 2015, 'A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome', Human Molecular Genetics, vol. 24, no. 24, pp. 7151-7158. https://doi.org/10.1093/hmg/ddv412
Didonna, Alessandro ; Isobe, Noriko ; Caillier, Stacy J. ; Li, Kathy H. ; Burlingame, Alma L. ; Hauser, Stephen L. ; Baranzini, Sergio E. ; Patsopoulos, Nikolaos A. ; Oksenberg, Jorge R. / A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 24. pp. 7151-7158.
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