Gene mutation found explaining multiple sclerosis
Although multiple sclerosis (MS) is seen to run in certain families, attempts to find genes linked to the disease have been elusive. For the first time, researchers are now reporting a gene mutation connected directly to the disease.
MS is a neurodegenerative disease in which the immune system attacks the myelin layer protecting nerves. This upset in the flow of information from the brain to the body, affects about 2 million people worldwide. In its more severe, progressive form, there is no good treatment available.
About 10% to 15% of MS cases appear to be hereditary, but until now genetic studies have found only weak associations between risk of developing MS and certain gene variants. This study has determined those people carrying the newly discovered mutation have a 70% chance of developing the disease.
Before 1950, most women with MS were advised not to become pregnant because it was believed pregnancy might make their MS worsen. Over the past 40 years, studies in hundreds of women with MS, have almost all come to the opposite conclusion: pregnancy reduces the number of MS relapses, especially in the second and third trimesters.
"This finding is critical for our understanding of MS. Little is known about the biological processes that lead to the onset of the disease, and this discovery has massive potential for developing new treatments that tackle underlying causes, not just symptoms."
Carles Vilariño-Güell PhD, Assistant Professor, Department of Medical Genetics, the University of British Columbia, Vancouver, Canada; and one of the study's senior authors.
In the current study, investigators reviewed materials from the Canadian Collaborative Project on Genetic Susceptibility to MS, a large database that contains genetic material from almost 2,000 families across Canada. The resulting work is published in the journal Neuron.
Researchers studied one family that had five cases of the disease spanning two generations. Using exome sequencing, researchers looked for rare coding mutations in all family members with the disease. After identifying a gene of potential interest, they searched their database and found the same mutation in another family with multiple cases of MS. Interestingly, all patients in both families with the same gene mutation had the progressive form of MS.
"The mutation we found, in a gene called NR1H3, is a missense mutation [when a single nucleotide change results in code for a different amino acid] which causes loss of function in its gene output, the LXRA protein. There is clear evidence to support this mutation has consequences on biological function, with defective LXRA protein leading to familial MS."
Weihong Song PhD, Neuroscientist, Canada Research Chair in Alzheimer's Disease at University of British Columbia, Vancouver, Canada, and one of the study's two senior authors.
MS symptoms are variable and unpredictable. No two people have exactly the same symptoms, and each person’s symptoms can change or fluctuate:
Clinically isolated syndrome (CIS). CIS refers to a first episode of neurologic symptoms lasting at least 24 hours, caused by inflammation or demyelination (loss of the myelin cover over nerve cells) in the central nervous system-CNS.
Progressive-relapsing MS — occasional relapses along the disease course, with relapses few and far between.
Relapsing-remitting disease which may transitiion into a less inflammatory Secondary-progressive disease which may or may not have any relapses.
Together with other members of the same protein family, LXRA controls regulation of gene transcription involved in the general stability, inflammation and immune factors affecting lipids (fatty acids) which help make up the myelin sheath that covers nerve axons. Mice without this gene have neurological problems along with a decrease in myelin production.
"One thing that's important to note is that although this mutation is present in only about 1 in 1,000 people with MS ... we've also found common variants in the same gene that are risk factors for progressive MS. So even in patients without the rare mutation, treatments that target this [LXRA protein] pathway could still be helpful."
Carles Vilariño-Güell PhD
Now researchers will be able to use the discovery of this mutation to develop cell and animal models for MS — research assets not previously available. Song: "These models will provide a good way for us to study the mechanism underlying the disease, as well as to screen for drugs that target it."
Interestingly, there is already interest in targeting this pathway for at least one other disease — atherosclerosis (hardening of the arteries).
"These are still early days and there is a lot to test, but if we are able to repurpose some of these [already in existence] experimental drugs, it could shorten the time it takes to develop targeted MS treatments."
Carles Vilariño-Güell PhD
The application of exome sequencing analysis in a family presenting a Mendelian form of MS has led to the identification of a pathogenic mutation in NR1H3. The p.Arg415Gln substitution was identified in seven MS patients from two unrelated families sharing a common disease haplotype (Table S2). The clinical phenotype observed in these patients is consistent with an unusual form of MS with a relapsing-remitting onset that rapidly becomes progressive or PPMS. Although the mutation was not observed in our healthy controls, it has been described in 21 individuals from the ExAC database (MAF = 0.0002), as well as three obligate carriers and an unaffected biological family member from this study, thus suggesting that additional genetic, epigenetic, or environmental factors may be necessary to develop disease. Therefore, these families appear to have a highly susceptible NR1H3 genetic background for MS, but an initial damage may be necessary to trigger the onset of disease. This incomplete penetrance is not unexpected for a highly heterogeneous and multifactorial disease such as MS.
This study was supported by the Canada Research Chair and Canada Excellence Research Chair programs, the Canadian Institute of Health Research, the Vancouver Coastal Health Research Institute, the Milan & Maureen Ilich Foundation, and the Vancouver Foundation.
Neuron (@NeuroCellPress), published by Cell Press, is a bimonthly journal that has established itself as one of the most influential and relied upon journals in the field of neuroscience and one of the premier intellectual forums of the neuroscience community. It publishes interdisciplinary articles that integrate biophysical, cellular, developmental, and molecular approaches with a systems approach to sensory, motor, and higher-order cognitive functions. Visit http://www.cell.com/neuron. To receive Cell Press media alerts, contact firstname.lastname@example.org.
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Jun 16, 2016 Fetal Timeline Maternal Timeline News News Archive
Myelin is about 40% water; the dry mass is about 70–85% lipids and about 15–30% proteins.
Some of the proteins are myelin basic protein (MBP, which makes up ~30% of myelin protein),
myelin oligodendrocyte glycoprotein, and proteolipid protein (PLP ~50% of myelin protein).
Image Credit: Wikipedia