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

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis.

Author information

1
Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
2
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.
3
Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
4
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
5
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
6
Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: weihong@mail.ubc.ca.
7
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: carles@can.ubc.ca.

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.

PMID:
27253448
PMCID:
PMC5092154
DOI:
10.1016/j.neuron.2016.04.039
[Indexed for MEDLINE]
Free PMC Article

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