Summary: Scientists have identified 12 genes linked to familial multiple sclerosis (MS). These discoveries offer a molecular explanation for the chronic inflammation, demyelination and neurodegeneration that characterize MS, and they highlight genetic targets that could guide the development of preventive therapies for people at elevated hereditary risk.
Source: University of British Columbia
An international research team led by the University of British Columbia reports a major genetic advance that could accelerate efforts to prevent and treat multiple sclerosis.
Published in PLOS Genetics, the study used whole-exome sequencing to analyze affected members of families with multiple cases of MS. By sequencing all known genes in at least three affected members from 34 multi-incident families, researchers examined genetic variation across 132 patients and their relatives. The analysis identified rare, likely pathogenic variants in 12 genes that appear to drive an overactive immune response targeting myelin, the insulating sheath around nerve fibers in the brain and spinal cord.
“These genes act like a lighthouse pointing toward the underlying causes of familial MS,” said lead author Carles Vilariño-Güell, assistant professor in the UBC Faculty of Medicine’s Department of Medical Genetics and a Michael Smith Scholar. “Knowing which genes are involved gives us a clearer path to model the disease and ultimately to pursue strategies that address its root causes rather than only treating symptoms.”
Multiple sclerosis is an inflammatory disease of the central nervous system in which immune cells damage myelin and harm neuronal function. While most MS cases do not cluster in families, Mendelian or familial forms have been observed. In this study, the identified variants occur in genes that regulate innate immunity and control the transcription and activation of inflammatory mediators, suggesting a common biological process that initiates persistent inflammation and neurodegeneration.
Of all people diagnosed with MS, only a minority—about 13 percent—are thought to have a clear genetic form of the disease. However, family members who carry the specific mutations reported in this study were estimated to have as much as an 85 percent lifetime risk of developing MS. That degree of penetrance underscores the potential value of these genes for understanding disease mechanisms, for identifying at-risk relatives, and for guiding preventive research.
The 12 candidate genes nominated by the study fall into several interconnected pathways implicated in immune regulation and inflammation. They include components of the fibrinolysis and complement systems (PLAU, MASP1, C2), genes involved in inflammasome assembly (NLRP12), regulators in Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), factors associated with nuclear receptor complexes (NCOA3), and genes coding for ion channels and exchangers (KCNG4, SLC24A6, SLC8B1). Collectively, these variants point to a disrupted network of immunological and pro-inflammatory mechanisms that likely initiate the cascade of demyelination and neuronal injury seen in familial MS.
“Current MS treatments focus on reducing relapses and controlling immune activity, but they do not fully halt disease progression,” Vilariño-Güell explained. “By identifying genetic variants that predispose families to MS and that nominate shared biological pathways, we can begin to create cellular and animal models that reproduce the disease’s early events. Those models are essential for testing targeted interventions aimed at preventing disease onset in genetically susceptible individuals.”
The research team plans to use the discovered mutations to build laboratory and animal models that mimic the biological processes leading to MS. These preclinical models will help evaluate whether interventions that modify the implicated pathways can prevent or delay disease development, and they could inform the design of personalized therapies for patients with specific genetic risks.
Funding: The study received support from the Canada Research Chair program, the Michael Smith Foundation for Health Research, the Canadian Institutes of Health Research, the Vancouver Coastal Health Research Institute, the Milan & Maureen Ilich Foundation and the Vancouver Foundation.
Source:
University of British Columbia
Media Contacts:
Cheryl Rossi – University of British Columbia
Image Source:
The image is in the public domain.
Original Research (open access):
“Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease”. Vilariño-Güell et al., PLOS Genetics. DOI: 10.1371/journal.pgen.1008180
Abstract (summary)
Whole-exome sequencing of 132 patients from 34 multi-incident MS families identified rare missense or nonsense variants in 12 genes of the innate immune system. These genes regulate transcription and activation of inflammatory mediators and belong to pathways including fibrinolysis and complement (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels/exchangers (KCNG4, SLC24A6, SLC8B1). The findings support a model in which dysregulated, interconnected immunological and pro-inflammatory pathways initiate the chronic inflammation, demyelination and neurodegeneration that characterize familial forms of MS.