Vancouver - A point mutation in control gene with an important function in lipid metabolism and the immune system has led to seven diseases of particularly rapidly progressing form of multiple sclerosis (MS) in two Canadian families. The discovery reported in Neuron (2016; 90: 948-954) provides new insights into the pathogenesis of the autoimmune disease, for which certain familial cluster is known.
Twin studies have shown that about 10 to 15 percent of the MS diseases have hereditary component, although it is rare for more than one member of family to become ill. It was therefore unusual for five out of eleven members over three generations in Canadian family to develop MS, which was also characterized by rapid progression without intermittent recovery phases.
The team led by Carles Vilariño-Güell from der The University of British Columbia in Vancouver had the entire exome, i.e. all genes that contain information for proteins, decoded in the sick and some healthy families. They came across gene that had led to two diseases in another family. All patients had progressive form of MS, which was normally only found in 15 percent of all patients.
The mutation was in gene called NR1H3. It was so-called missense mutation. It leads to the replacement of the amino acid arginine for glutamine, which has led to the formation of functionless gene product. The gene product LXRA is receptor in the cell nucleus that is supposed to influence lipid metabolism, inflammatory processes and innate immunity.
In mice, the failure of LXRa is associated with neurological disorders that can be attributed to decrease in myelin production, leading to the pathogenesis of MS in humans fits, which is triggered by an autoimmune attack on the very protective covering of the nerves. A further study on 2,053 MS patients and 799 healthy controls showed that gene variant that presumably does not lead to complete failure of the gene is associated with 35 percent increased risk of the primary progressive variant of MS.
Vilariño-Güell estimates that the missense mutation is responsible for only about one in thousand MS diseases. Screening MS patients (and their relatives) is therefore unlikely to be worthwhile, especially since the finding does not currently open up any therapeutic options. However, so-called LXA agonists have been developed in recent years. They should be used to treat atherosclerosis, because LXR (the abbreviation for "Liver X receptor") also intervenes in the regulation of cholesterol metabolism. However, the clinical trials were stopped due to severe side effects.