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

研究成果: Contribution to journalArticle査読

12 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)7151-7158
ページ数8
ジャーナルHuman molecular genetics
24
24
DOI
出版ステータス出版済み - 2015
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 遺伝学
  • 遺伝学(臨床)

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