Nuclear Receptor NR1H3 in Familial Multiple Sclerosis
Authors: Jay P Ross
Weihong Song
Anthony L Traboulsee
Colin J Ross
Talitha Greenwood
Carles Vilariño-Güell
Mary Encarnacion
Cecily Q Bernales
Irene M Yee
Si Zhang
Galen Wright
Joshua D Lee
Zhe Wang
A Dessa Sadovnick
Madonna de Lemos
Journal: Neuron (2016)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Multiple sclerosis; NR1H3; p.Arg415Gln; progressive disease; genetic mutation
Affiliations: Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada., Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada., Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada., Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada., Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada., Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: ., Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: .

Abstract:  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. 

Retracted: No

PubPeer comments:
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 Besides the PubMed Commons comments, there is a preprint entitled  NR1H3 p.Arg415Gln Is Not Associated To Multiple Sclerosis Risk that calls into question the conclusions by Wang et al., 2016 paper https: www.biorxiv.org content 10.1101 061366v3 From the Abstract:  A recent study by Wang et al claims the low-frequency variant NR1H3 p.Arg415Gln is pathological for multiple sclerosis and determines a patientu2019s likelihood of primary progressive disease. We sought to replicate this finding in the International MS Genetics Consortium (IMSGC) patient collection, which is 13-fold larger than the collection of Wang et al, but we find no evidence that this variant is associated either with MS or disease subtype. Wang et al also report a common variant association in the region, which we show captures the association the IMSGC reported in 2013. Therefore, we conclude that the reported low-frequency association is a false positive, likely generated by insufficient sample size. The claim of NR1H3 mutations describing a Mendelian form of MS - of which no examples exist - can therefore not be substantiated by data. ,