Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Neuron. 2016 Jun 1;90(5):948-54. doi: 10.1016/j.neuron.2016.04.039.


Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss and neuronal dysfunction. Despite the aggregation observed in some families, pathogenic mutations have remained elusive. In this study, we describe the identification of NR1H3 p.Arg415Gln in seven MS patients from two multi-incident families presenting severe and progressive disease, with an average age at onset of 34 years. Additionally, association analysis of common variants in NR1H3 identified rs2279238 conferring a 1.35-fold increased risk of developing progressive MS. The p.Arg415Gln position is highly conserved in orthologs and paralogs, and disrupts NR1H3 heterodimerization and transcriptional activation of target genes. Protein expression analysis revealed that mutant NR1H3 (LXRA) alters gene expression profiles, suggesting a disruption in transcriptional regulation as one of the mechanisms underlying MS pathogenesis. Our study indicates that pharmacological activation of LXRA or its targets may lead to effective treatments for the highly debilitating and currently untreatable progressive phase of MS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Female
  • Gene Expression / genetics
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Liver X Receptors / genetics*
  • Male
  • Middle Aged
  • Multiple Sclerosis, Chronic Progressive / genetics*
  • Mutation
  • Pedigree
  • Phenotype
  • Protein Isoforms / genetics


  • Liver X Receptors
  • NR1H3 protein, human
  • Protein Isoforms