Novel mutation in the recently identified LRRK2 gene causes parkinsonism

Neuroscientists at Mayo Clinic in Jacksonville, Fla., leading a team of researchers in the United States and Europe, have discovered that a novel mutation in the recently identified LRRK2 gene causes parkinsonism in several North American and European families.

Their findings will be reported in the April edition of the American Journal of Human Genetics. The disease-causing G2019S mutation in the LRRK2 gene is the first time a genetic cause has been associated with typical, late-onset Parkinson's disease.

The researchers found the mutation by DNA sequencing of the LRRK2 gene in families with parkinsonism. These families came from the United States, Norway, Ireland and Poland. Family members of the patients with the G2019S mutation were subsequently screened, and 22 of 42 were found to carry the same mutation. Seven of them were already diagnosed with Parkinson's disease. The mutation was absent in more than 2,000 healthy control individuals. Subsequent screening identified several patients with sporadic Parkinson's disease (i.e., no family history) who were positive for this mutation. Interestingly, all G2019S patients shared a genetic pattern indicating a common, although ancient, ancestor.

Parkinsonism is a syndrome characterized by resting tremor, rigidity, slow movement and postural instability. The most common form of Parkinson's disease, which manifests late in life, was thought to be sporadic. However, these findings indicate a genetic component of the disease. "It's a small number of cases," says Mayo Clinic neuroscientist Matthew Farrer, Ph.D., whose lab sequenced the gene, "but it will be insightful for creating models of Parkinson's and extrapolating from that to the disease in general."

Age of onset of clinical symptoms of the disease varied, even within the same family. Within one family alone, age of symptom onset ranged from 39 to 78 years. In addition, the older the patient, the more likely he or she exhibited symptoms.

"From a research point of view, this is the first time we could identify what appears to be typical Parkinson's disease cases before people develop symptoms," Farrer says. "We know if someone inherits the mutation they are going to get Parkinson's disease."

Farrer and his colleagues are beginning to explore the cellular role of the LRRK2 protein and the reason it causes disease when the mutant gene is present. "It's an exciting time in the study of the genetics of Parkinson's disease," says Farrer. "There are already clinical trials of mixed-lineage kinase inhibitors that may be targeted at this form of the disorder. Our objectives are to understand the molecular events that cause Parkinson's disease and to target therapeutics to halt its progression."