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Publications of the Week

Exome Sequencing in Multiple Sclerosis Families Identifies 12 Candidate Genes and Nominates Biological Pathways for the Genesis of Disease

By June 10, 2019June 11th, 2019No Comments

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This week we profile a recent publication in PLOS Genetics from Dr. Carles Vilariño-Güell (pictured) at UBC.

Can you provide a brief overview of your research interests?

In my research career, I focus predominantly on the genetic characterization of familial forms of complex diseases with a focus on neurodegenerative and immunological disorders. The reason for this focus is because the study of families with high incidence of disease provides the means for the identification of pathogenic mutations that can inform the molecular mechanisms responsible for the onset of disease. Examples include the identification of pathogenic mutations in VPS35 and DNAJC13 for Parkinson’s disease, and NR1H3 for multiple sclerosis. These genetic discoveries provide the foundations for the generation of animal and cellular models capable of recapitulating human genetic etiology, and the tools for the development of novel treatments and personalized medicine approaches. This is highlighted by our recently developed animal model of multiple sclerosis based on the pathogenic mutation identified in NR1H3, as this model presents an immune imbalance, neuronal degeneration and de-myelination similar to that observed in multiple sclerosis patients, thus representing the first model of multiple sclerosis based on human disease.

What is the significance of the findings in this publication?

This study provides a better understanding of the biological processes leading to the onset of multiple sclerosis. Most treatments for multiple sclerosis target the adaptive immune response (T-cells and B-cells) and may ameliorate the patients’ clinical symptoms, but they have little or no effect on disease onset and progression. The 12 genes harboring pathogenic mutations for multiple sclerosis identified in our study have biological functions in linked innate immune pathways (Figure 3 in the manuscript), and suggest that the dysregulation of innate immunity, not adaptive, is the initial step towards the development of disease. Therefore, future treatments developed towards repairing these disrupted innate immune pathways have the potential to provide more effective therapeutics, and potentially preventative treatment for high risk individuals.

This work was funded by:

The work was funded by the Canada Research Chair program, 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.

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