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.

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SUMMARYMultiple 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.

Identifying rare genetic variants that drive the onset of disease is challenging, even before considering the additional genetic and environmental influences that likely exist in complex diseases. We recently published a study proposing a rare variant in the NR1H3 gene (p.R415Q, rs61731956) as responsible for the onset of multiple sclerosis (MS) in two multi-incident families (Wang et al., 2016). This publication has generated much discussion, and fortunately the possibility to validate a finding or prove it spurious can occur rapidly in genetic studies. All novel discoveries must be replicated, and best efforts should be made to ensure that these replications use the appropriate samples and approach, and provide the correct interpretation of the results. This Matters Arising Response paper addresses the Minikel and MacArthur (2016) and The International Multiple Sclerosis Genetics Consortium (2016) Matters Arising papers, published concurrently in Neuron.

Abstract:Objective:To determine whether different health care systems may affect reproductive decision-making among patients with Multiple Sclerosis (MS), we describe the reproductive practices and attitudes of Canadian MS patients ascertained from the multidisciplinary MS Clinic at Hôpital Notre-Dame in Montreal, Quebec (NDMSC), in comparison to those of matched American selfregistrants from the database of the North American Research Committee on Multiple Sclerosis (NARCOMS).Methods:A total of 665 self-administered questionnaires on reproductive practices were sent out to eligible attendees attending the NDMSC. The short questionnaires were completed and returned to the authors in an anonymous format for analysis.Results:A total of 459 completed questionnaires were returned. The majority of NDMSC respondents (72.5%) and NARCOMS subset (75.2% females), did not encounter a pregnancy following diagnosis of MS. The most common MS-related reason for this decision was “symptoms interfering with parenting” (75.0% for the NDMSC, 72.6% for the NARCOMS). The most commonly reported non-MS-related reason was “a completed family” by the time of diagnosis in both the NDMSC and NARCOMS subset (58.0%, 40.4%, respectively). Concerns about financial issues both related and unrelated to MS were also commonly reported by males and females in both cohorts but significantly more so among the NARCOMS participants.Conclusion:These results indicate that reproductive decisions of MS patients are highly affected by their illness and its associated disability, regardless of the available health care program. Health care providers should discuss their patients' reproductive needs and perceptions to help them make more informed decisions.