A combination of mutations in two genes makes members of a Canadian family a 7-in-10 chance of developing multiple sclerosis (MS) — a radical increase from the 1-in-1,000 risk among the general population, according to a study that illustrates the huge impact certain genes can have on disease development.
Interestingly, the genes are involved in both immune processes and phagocytosis — a process by which cells get rid of cellular debris and which has not been linked to MS before.
Last year, the University of British Columbia research team also discovered a mutation that caused a familial type of progressive MS in a Canadian family.
Their study, “Purinergic receptors P2RX4 and P2RX7 in familial multiple sclerosis,” appeared in the journal Human Mutation.
Researchers usually view MS as resulting from the small effects of numerous genes that come together with unfortunate environmental factors to cause disease. Yet the team challenges the notion that MS is not an inherited condition by demonstrating that in rare cases it, indeed, can be. It also opens up the possibility of genetic screening in people with a family history of the disease.
In this study, the research team homed in on two genes that were linked to MS in earlier studies. A biobank holding blood samples of 4,400 people with MS allowed them to easily sequence the two genes in samples from 193 MS patients and 100 controls.
They found two mutations in one of the genes, called P2RX7, and one mutation in the other, called P2RX4, in the affected family.
To explore whether the mutations really changed the way cells work, they grew cells with the mutations in the laboratory and observed how they differed from normal cells. They easily spotted the effects of these mutations and what impact they had on both immune processes and phagocytosis.
“This is the first time that problems with phagocytosis have been linked to MS, and provides scientists with a better understanding the disease’s origins and targets for developing new treatments,” senior study author Carles Vilarino-Guell, an assistant professor of medical genetics, said in a press release.
People in the identified family had a relapsing form of MS. Although the combination of mutations in the two genes caused MS in six out of 13 siblings and first cousins, researchers found that some of them carried the mutation without getting sick. This suggests that other factors — either genetic or environmental — can counteract the effects of the mutations.
The Canadian team collaborated with colleagues at Australia’s Florey Institute of Neuroscience and Mental Health.
Besides proving that inherited MS does exist, the study suggests genetic screening in families with many affected members. If doctors identify these mutations in a person who has not yet developed symptoms, they can monitor that patient to detect symptoms and brain changes at an early stage.
People with known mutations can also try to reduce their risk of disease by, for instance, taking vitamin D supplements or quitting smoking, researchers suggested.