Mutations to NR1H3 Gene May Have Implications for Pathogenesis of Progressive MS

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Mutations to NR1H3 Gene May Have Implications for Pathogenesis of Progressive MS
Mutations to NR1H3 Gene May Have Implications for Pathogenesis of Progressive MS

Pathogenic mutations of the NR1H3 gene were directly linked to progressive forms of multiple sclerosis (MS) in a recent familial study reported in Neuron.1 Analysis of genetic samples from the Canadian Collaborative Project on Genetic Susceptibility to MS (a database of over 2000 families) identified 7 individuals from 2 unrelated families who all had the same mutation to NR1H3, and who had all presented with severe and rapidly progressive MS.

Senior author Weihong Song, MD, PhD, a Canada Research Chair in Alzheimer's Disease at the University of British Columbia, explained that the mutation “is a missense mutation that causes loss of function of its gene product, LXRA protein," which together with LXRB is involved in transcriptional regulation of genes responsible for transport, catabolism, and elimination of cholesterol.

Alterations to LXRA caused by mutant NR1H3 in the study suggested that the resulting lipid dysfunction plays a role in the mechanisms of MS. A 2002 study by Ling Wang and colleagues2 in LXRA-LXRB double knockout mice reported abnormal lipid accumulation in the brain, along with axonal atrophy, neuronal loss, and astrogliosis. Later studies3,4 showed decreased myelin protein quantities in these mice, despite increased protein transcript expression, resulting in thinner myelin sheathing and dysfunctional remyelination.

"There is clear evidence to support that this mutation has consequences in terms of biological function, and the defective LXRA protein leads to familial MS development," Dr Song observed.

"Little is known about the biological processes that lead to the onset of the disease, and this discovery has massive amounts of potential for developing new treatments that tackle the underlying causes, not just the symptoms," reported study co-author Carles Vilariño-Güell, PhD, Assistant Professor in the Department of Medical Genetics at the University of British Columbia (UBC) in Vancouver, BC.

Although the NR1H3 mutation is rare and can be implicated in only about 1000 of the 2 million cases worldwide, common variations within the same gene were associated with a higher risk of progressive MS, pointing to an important pathway for the development of therapeutic interventions. "So even if patients don't have the rare mutation, treatments that target this pathway would likely be able to help them," Dr Vilariño-Güell said.

References

  1. Wang Z, Sadovnick AD, Traboulsee AL, et al. Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. Neuron. 2016;90(5):948-54.
  2. Wang L, Schuster GU, Hultenby K, et al. Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration. Proc Natl Acad Sci. 2002;99:13878–13883.
  3. Makoukji J, Shackleford G, Meffre D, et al. Interplay between LXR and Wnt/b-catenin signaling in the negative regulation of peripheral myelin genes by oxysterols. J Neurosci. 2011;31:9620–9629.
  4. Meffre D, Shackleford G, Hichor M, et al. Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum. Proc. Natl. Acad. Sci. 2015;112:7587–7592.
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