Two copies of G2019S Parkinson's gene mutation doesn't lead to more severe disease

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In most diseases with a genetic cause or component, two copies of a bad gene lead to more severe visible manifestation of the disease. Researchers expected to see worse symptoms, the disease start earlier in life and a shorter life span for those with two copies of the LRRK2 gene with the G2019S mutation. "That proved not to be the case," says Mayo Clinic neurologist Zbigniew Wszolek, M.D.

Wszolek formed an international consortium that compared the clinical features of Parkinson's disease in the two groups. "It's puzzling," he says. "More studies are needed. More patients need to be identified and, hopefully, more basic science research is going to be performed to find out why."

The G2019S mutation is the most common of the 20 identified LRRK2 disease-causing mutations. There are six known genes that cause familial Parkinson's disease, but only one, the G2019S mutation of the LRRK2 gene, has been associated with previously unexplained cases of Parkinson's disease. Wszolek and his colleagues hope that studying the ways in which these genes cause disease, especially the G2019S mutation, will lead to improved treatments and even a cure. "We are all united by the common drive to learn more about this disease, to help the people with this illness and to bring us closer to curative treatments," Wszolek says. "And this may be a step in that direction."

By pooling their studies from around the globe, Wszolek and his colleagues found 26 people with the G2019S mutation in both copies of their LRRK2 gene-one inherited from the mother and the other from the father. Interestingly, three patients with the dual mutation exhibited no clinical signs of Parkinson's disease, an indication that the gene has incomplete penetrance.

This concept means having the gene mutation alone does not lead to developing severe symptoms or even developing any signs of the disease 100 percent of the time. "One may need some additional factors, either genetic or environmental, which work either to produce the disease or to protect one from developing it," Wszolek says.

This latest finding supports the theory many hold that the majority of Parkinson's disease cases may only be explained by the interaction of a number of genes or a genetic and environmental interaction.

Wszolek and his colleagues found all patients in their study, whether they had one or two G2019S mutations, had asymmetric onset of symptoms, most often tremor, no male or female preponderance, and both groups had a similar range in the age in which symptoms began.

In 2004 Wszolek was one of the researchers who discovered the LRRK2 gene caused parkinsonism. He was also part of the team that discovered the G2019S mutation causes parkinsonism in several North American and European families. That was the first time a genetic cause had been associated with typical, late-onset Parkinson's disease.

Mayo Clinic, Jacksonville