A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients

Julien Pothlichet, Timothy B. Niewold, Damien Vitour, Brigitte Solhonne, Mary K. Crow, Mustapha Si-Tahar

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signalling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon (IFN) and other proinflammatory mediators and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I IFN production and absence of anti-RNA-binding protein autoantibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral IFN pathway in vivo in humans and is associated with a novel sub-phenotype in SLE. This study demonstrates the utility of functional data in selecting rare variants for genetic association studies, allowing for fewer comparisons requiring statistical correction and for alternate lines of evidence implicating the particular variant in disease.

Original languageEnglish (US)
Pages (from-to)142-152
Number of pages11
JournalEMBO Molecular Medicine
Issue number3
StatePublished - Mar 2011


  • Cell signalling
  • Immune response
  • Lupus
  • Polymorphisms
  • Virus

ASJC Scopus subject areas

  • Molecular Medicine


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