Genetic mutation explaining progressive multiple sclerosis identified

Scientists have identified a mutation strongly associated with the progressive form of multiple sclerosis (MS). In a paper in Neuron they report seven individuals from two unrelated families who showed symptoms of rapidly progressive MS carried a mutation in the gene NR1H3 which regulates inflammation and immunity. The scientists also found common variants in this gene are associated with elevated risk for MS and suggest it presents a new drug therapy target for MS treatment.


Dr. Michael Demetriou, Director, National Multiple Sclerosis Society Designated Comprehensive Care Clinic; Professor, Neurology, School of Medicine, University of California, Irvine (webpage)

Expertise: multiple sclerosis, autoimmunity, human genetics, metabolism, glycobiology

“The authors describe a rare form of familial multiple sclerosis and discovered a highly associated mutation in two families. However, the mutation was not completely predictive. So, while the mutation is strongly linked to MS, it’s not 100%. The mutation also represents a very rare form of MS. This mutation, though rare, is an important and very interesting finding that is relevant to the MS community at large.

“The researchers also found other nucleotide variations that are associated with progressive multiple sclerosis, which is a unique and valuable finding. However, these mutations were only weakly associated with MS, meaning that they do contribute to risk but are only a minor component and that there must be many other contributing risk factors.

“There is no one cause for multiple sclerosis. There are multiple contributing factors, both environmental and genetic. The authors have identified one contributing factor, but I wouldn’t say they found a cause.

“The study does suggest that targeting this signaling pathway may be an excellent strategy for treating progressive multiple sclerosis. As we currently don’t have any drug therapies for progressive MS, this would be a very big deal. There are some treatments in the pipeline but this represents a potentially new therapy for progressive MS. Drug treatments may be many years away but this study suggests that targeting this pathway may have some benefit.”


Dr. Michelle Apperson, Director, Multiple Sclerosis Program; Assistant Clinical Professor, University of California, Davis (webpage)

Expertise: gene expression and biomarkers in multiple sclerosis, multiple sclerosis immunology

“This is an interesting study that has identified a gene mutation associated with multiple sclerosis in seven patients from two different families.

“Multiple sclerosis (MS) is thought to be a chronic, immune mediated disorder leading to destruction of myelin, the insulation around nerves in the brain. The cause of multiple sclerosis has been thought to be from an environmental exposure in the context of a genetic predisposition. Large studies have identified multiple potential ‘risk’ and ‘protective’ gene differences. However, it is uncertain in individual patients which genes or combination of genes are playing a role in the development of MS.

“This study identifies a single gene mutation involved in two families with a genetic pattern of multiple sclerosis inheritance. It is interesting that several carriers of that gene mutation appeared unaffected. This could be because there are other ‘protective’ genes or because of differences in environmental exposures. The authors discuss the possibility of developing medications targeting the effects of this gene mutation as a possible treatment for affected patients. This illustrates the concept of personalized medicine in multiple sclerosis. In the future, we may be able to look at a patient’s genetic profile or other biomarkers and choose a medication that best fits that individual.

“A limitation of the study is the small number of patients detected (authors estimate this gene is found in only 1 in 1,000 multiple sclerosis patients). Larger studies in families with MS will be needed to confirm these results and identify other genetic mutations.”


Dr. Simon Gregory, Director, Genomics and Epigenetics, Duke Molecular Physiology Institute; Associate Professor, Department of Medicine, Duke University School of Medicine (webpage)

Expertise: genetics of MS, mechanisms of MS development and progression, MS biomarker development

“Multiple sclerosis (MS) is a complex, chronic disease. The difficulty of identifying the cause of MS is that the disease develops in the context of hundreds of known DNA risk variants that combine with unknown environmental factors to trigger disease. To date, the majority of genetic studies have focused on the most common form of the disease, relapsing remitting MS (RR-MS), which represents approximately 85% of the 2 million MS patients worldwide. The lower frequency of the remaining forms of MS, including primary progressive MS (PP-MS), do not yield enough statistical power to adopt the genome wide approaches used for RR-MS genetic discoveries.

“Here, the authors present intriguing data that explores the genetic causes of MS over three generations of a family who initially show symptoms of relapsing remitting MS (RR-MS) and then develop primary progressive MS (PP-MS). The somewhat predictable inheritance patterns of PP-MS in the family allowed the investigators to sequence genomic regions of affected individuals before filtering for rare DNA variants that segregated with the disease. They identified a DNA variant in the NR1H3 gene, which was then validated in an unrelated family.

“The importance of the variant in NR1H3 and the association of NR1H3 with PP-MS is underscored by its evolutionary conservation within NR1H3’s protein product (LXRA). Notably, this conserved variation has a disruptive effect on the LXRA protein. LXRA is known to control inflammation, innate immunity and lipid regulation. These are clearly important factors for a disease in which inflammation constitutes an initiating event, it is thought to be immune driven, and lipid loss (demyelination of axons) contribute to clinical severity.

“The identification of this gene and its known activation by cholesterol derivatives presents an exciting novel class of drugs or pathways to modulate. Even so, the study requires replication in independent PP-MS sample collections. Also, the presence of family members who carry the risk DNA variant but don’t develop the disease suggests that other genetic factors are important. The study represents critical genetic and potential mechanistic findings in a sub-type of the MS population who, to date, have been devoid of treatment and mechanistic understanding.”


Declared interests (see GENeS register of interests policy):

None declared.


Nuclear receptor NR1H3 in familial multiple sclerosis‘ by Wang et al., published in Neuron on Wednesday, June 1st, 2016

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