title: Nuclear Receptor NR1H3 in Familial Multiple Sclerosis.
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.
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: A Dessa
authors.initials: AD
authors.lastname: Sadovnick
authors.affiliation: Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Traboulsee
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Ross
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Cecily Q
authors.initials: CQ
authors.lastname: Bernales
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Mary
authors.initials: M
authors.lastname: Encarnacion
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Yee
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Madonna
authors.initials: M
authors.lastname: de Lemos
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Talitha
authors.initials: T
authors.lastname: Greenwood
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Lee
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Galen
authors.initials: G
authors.lastname: Wright
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Si
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: weihong@mail.ubc.ca.
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: carles@can.ubc.ca.
authors.forename: Carles
authors.initials: C
authors.lastname: Vilariño-Güell
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D000071518:Liver X Receptors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics
chemical_list: D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D020033:Protein Isoforms