A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients. - Institut Pasteur Access content directly
Journal Articles EMBO Molecular Medicine Year : 2011

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

Abstract

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.

Domains

Innate immunity
Fichier principal
Vignette du fichier
M._Si-Tahar.pdf (984.5 Ko) Télécharger le fichier
Origin Files produced by the author(s)
Loading...

Dates and versions

pasteur-00562505 , version 1 (03-08-2011)

Licence

Identifiers

Cite

Julien Pothlichet, Timothy B. Niewold, Damien Vitour, Brigitte Solhonne, Mary K. Crow, et al.. A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients.: Impact of a loss-of-function MAVS variant on SLE. EMBO Molecular Medicine, 2011, 3 (3), pp.142-52. ⟨10.1002/emmm.201000120⟩. ⟨pasteur-00562505⟩

Collections

INSERM PASTEUR
186 View
311 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More