LRRK2 gene variant may be cause of Parkinson’s in Europe: Study
Rare mutation found in 17 people of European ancestry using genetic data
A rare mutation in the LRRK2 gene found in 17 individuals with Parkinson’s disease or a family history of Parkinson’s — all of European ancestry with a shared genetic background — appears to be a likely cause of the condition, according to a study of thousands of people.
The study, “The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population,” was published in the journal npj Parkinson’s Disease by an international team of researchers. The team drew on data from the Global Parkinson’s Genetics Program and other datasets to cull information from more than 50,000 people.
“We identified [an] LRRK2 …. variant in three families and six additional unrelated cases,” the researchers wrote. “We provide evidence that [this] LRRK2 [mutation] is pathogenic,” meaning disease-causing.
According to the team, “including this variant in the genetic screening of [Parkinson’s] patients, particularly those of Central-Eastern European origin, may be beneficial for the variant carriers to be included in ongoing gene-specific clinical trials.”
Not everyone with mutations in the LRRK2 gene will develop Parkinson’s, a condition that progressively affects motor control. However, it is one of the most common genetic causes of the familial form of the disease, research has shown. The LRRK2 gene codes for an enzyme of the same name that’s often overactive in Parkinson’s.
Researchers identify LRRK2 gene mutation as disease-causing
In their study, the researchers ultimately focused on one particular mutation, called p.L1795F. It’s known to increase the LRRK2 enzyme’s activity, but further evidence was needed to confirm whether or not it was disease-causing.
According to the researchers, potential confirmation was important “for diagnosis, genetic counseling, and even more for treatment, particularly now that LRRK2-specific clinical trials are underway.”
Initially, the team screened genetic data from 16,351 individuals with and without Parkinson’s to identify rare mutations in LRRK2 and other genes. They focused on variants that appeared multiple times and segregated with Parkinson’s, meaning they were passed down in families along with the disease.
Among these, they identified nine individuals carrying the LRRK2 p.L1795F mutation. These nine came from two families. In one family, four individuals with Parkinson’s carried the mutation, while in the other family, the mutation was found in one individual with Parkinson’s and two without symptoms at ages 55 and 76. Two additional carriers had Parkinson’s and a family history of the disease.
The researchers then extended genetic screening to an additional 64,607 individuals with and without Parkinson’s, and identified four more carriers, three of whom had Parkinson’s disease.
A separate search in another dataset identified a family with four carriers of the LRRK2 p.L1795F mutation — three with Parkinson’s and one without symptoms.
“In total, we identified 17 individuals carrying this variant across all the datasets,” the researchers wrote.
We … propose LRRK2 [gene variant] p.L1795F as a cause of [Parkinson’s], especially in the European population.
Most carriers (70.6%) were women, and all had a family history of Parkinson’s. The patients’ ages at symptom onset ranged from ages 36 to 66, with a median of 54.5 years.
The majority of those diagnosed with Parkinson’s showed typical symptoms, starting asymmetrically, or on one side of the body, and responding well to medication. Limited data were available on nonmotor symptoms. Cognitive function was generally well preserved.
The mutation is rare and found in European populations, the team concluded. Specifically, all 17 carriers in this study were of European ancestry, and the mutation was absent in more than 15,000 individuals from other backgrounds.
“We therefore propose LRRK2 p.L1795F as a cause of [Parkinson’s], especially in the European population,” the researchers wrote.
Analysis of shared genetic segments among carriers identified a common genetic background, suggesting that the LRRK2 p.L1795F mutation came from a single ancestor.
“Including those reported in the literature, this brings the total to 22 clinically affected carriers of European ancestry,” the researchers wrote.
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