Parkinson’s Patients with Common Mutation Possibly at Earlier Onset Risk if Other Gene Defect Found

People carrying the most common Parkinson’s disease-related mutation in the LRRK2 gene may start showing symptoms at an earlier age if they also have a mutation in another gene.

The findings prompted researchers to suggest that tests for this newly identified mutation could be valuable for genetic counseling of LRRK2 mutation carriers, and also inform clinical trial design. However, others point to limits in researchers’ knowledge of how the two mutations are related, saying this is cause enough to wait before implementing such changes.

The study, “DNM3 and genetic modifiers of age of onset in LRRK2 Gly2019Ser parkinsonism: a genome-wide linkage and association study,” was published in the journal The Lancet Neurology.

Although the Gly2019Ser mutation in the LRRK2 gene is the most common genetic risk factor for Parkinson’s, far from everyone carrying the mutation develops the disease. In people of European descent, only 1% of carriers have Parkinson’s, while 13%–30% of Ashkenazi Jewish and up to 40% of North African Arab-Berber people carrying the mutation get Parkinson’s disease.

The age at which people start showing symptoms also varies widely, making researchers suspect that other factors, either genetic or environmental, modify the effect of the LRRK2 mutation.

Researchers from the University of British Columbia in Canada recruited 41 Arab-Berber families with Parkinson’s disease and LRRK2 Gly2019Ser mutations to look for genetic factors impacting the risk of disease. The group consisted of 150 Parkinson’s patients and 103 unaffected family members.

Using a genome-wide linkage analysis — a method allowing researchers to map a particular region in the DNA that tends to get inherited with the disease — the research team identified a part of chromosome 1.

Focusing on this region, researchers examined another group of 232 unrelated Arab-Berber LRKK2 mutation carriers. In this way, they could further narrow down the DNA stretch that seemed relevant, and found that a particular mutation could be used as a tag for earlier onset disease.

People carrying the mutation in the DNM3 gene were, on average, 12.5 years younger when they first experienced symptoms, compared to non-carriers. Finally, the team confirmed the finding in a group of 263 individuals from Algeria, France, Norway, and North America.

The finding does not necessarily mean that the function of DNM3 itself affects the development of  Parkinson’s disease. Researchers stated that the mutation is a so-called haplotype tag — marking an area of the DNA that tends to get inherited together.

Although there is some evidence that DNM3 is faulty in mice with the LRKK2 mutation, researchers from Mayo Clinic in Jacksonville, Florida, were more cautious in their interpretation of the findings. They underscored that it is crucial that other researchers replicate the experiments, as genetic studies often produce findings that are not seen in other groups of people.

They also stressed that other regions identified in the study were linked to disease onset. In addition, since the study only indicated that the region of the chromosome, and not the DNM3 gene itself, may affect the age of disease onset, researchers need to search for the particular gene causing the association.

They argued that such studies need to demonstrate the molecular events that speed up neurodegeneration in Parkinson’s disease before the newly identified mutation can be incorporated in clinical tests.