Mutations in ITSN1 gene linked with higher risk of Parkinson’s
While rare, these variants mostly in people with earlier onset disease
Mutations that inactivate a gene called ITSN1 are associated with an increased risk of Parkinson’s disease, particularly at younger ages, a large-scale database study reports.
Its researchers speculated that the protein encoded by the ITSN1 gene or related proteins might be viable targets to treat Parkinson’s.
The study, “Loss-of-function variants in ITSN1 confer high risk of Parkinson’s disease,” was published in npj Parkinson’s Disease.
Study into less common mutations that could be cause of Parkinson’s
While the causes of Parkinson’s disease are not fully understood, it’s clear that genetics plays a role in at least some cases. Mutations in several genes have been linked with an increased risk of Parkinson’s, and there are likely additional genes that affect Parkinson’s risk but not yet discovered.
To identify Parkinson’s-related mutations, scientists typically rely on an analytical strategy called genome-wide association studies (GWAS). Put simply, GWAS involves comparing the frequency of specific genetic mutations in individuals with Parkinson’s to those without the condition. A higher prevalence of a particular mutation among patients suggests an association between the mutation and the disease.
A limitation of this approach is that it looks for individual mutations, and as a result, mutations that are individually very rare often don’t yield statistically meaningful results.
A team led by scientists at deCODE Genetics (a subsidiary of Amgen based in Iceland) applied a slightly different strategy. Instead of looking for individual mutations, they searched for mutations that would be expected to inactivate genes, known as a loss of function mutation. Since all the inactivating mutations in a given gene would be expected to have the same effect on genetic activity, they can be analyzed collectively.
The scientists applied this approach to European datasets as well as a U.S. database — the Accelerating Medicines Partnership Parkinson’s disease — encompassing in total more than 12,000 people with Parkinson’s and more than 780,000 people without it. The team has made their entire dataset available to the research community, noting these data “will hopefully become a useful resource in future [Parkinson’s] studies.”
Disease risk seen to rise by seven times with mutations in ITSN1 gene
Results suggested that mutations which inactivate the ITSN1 gene are associated a more than seven times increase in the risk of Parkinson’s.
Among Parkinson’s patients, individuals carrying a loss of function ITSN1Â mutation tended to have an earlier age at disease onset, by about eight years on average, than those without the mutation. The youngest patient with this mutation was diagnosed at age 27, the researchers noted.
The ITSN1 gene provides instructions to make a protein called intersectin-1 (abbreviated ITSN1). This protein normally works in concert with another protein, CDC42, to regulate the cytoskeleton, which is the network of proteins that help give cells their structure, just as a person’s skeleton gives the body its structure.
CDC42 has been previously implicated in Parkinson’s development, so the researchers speculated that these two proteins may be viable therapeutic targets in the disease. Specifically, they postulated that defects in these proteins might lead to problems with synaptic transmission — the process by which nerve cells release signaling molecules to communicate with other nerves, which is highly dependent on a functional cytoskeleton.
“Direct modulation of CDC42 or its upstream regulator, ITSN1, could be exploited as therapeutic avenue” for Parkinson’s, the researchers concluded.
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