New gene variants present in 3 percent of all ALS patients
Variations in a gene with multiple functions in neurons are present in approximately 3 percent of all cases of ALS in North American and European populations, both sporadic and familial, making it one of the most common genetic causes of the disease, according to a paper. Led by John Landers, PhD, professor of neurology at UMass Medical School and Jan Veldink, PhD, at University Medical Center Utrecht in the Netherlands, the research was supported by The ALS Association through Project MinE, an international collaboration for gene discovery in ALS, and funded through ALS Ice Bucket donations.
ALS (amyotrophic lateral sclerosis) is a progressive neurodegenerative disease that affects neurons in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. While 10 percent of ALS is familial, meaning it’s genetic, the other 90 percent of ALS cases are considered sporadic, or without a family history. However, it’s very likely that genetics contribute, directly or indirectly, to a much larger percentage of ALS cases.
“The discovery of NEK1 highlights the value of big data in ALS research,” said Lucie Bruijn, PhD, MBA, of The ALS Association. “The sophisticated gene analysis that led to this finding was only possible because of the large number of ALS samples available. The ALS Ice Bucket Challenge enabled The ALS Association to invest in Project MinE’s work to create large biorepositories of ALS biosamples that are designed to allow exactly this kind of research and to produce exactly this kind of result.”
The new gene, called NEK1, was discovered through a genome-wide search for ALS risk genes in more than 1,000 ALS families, and was independently found through different means in an isolated population in the Netherlands. Further analysis in more than 13,000 sporadic ALS individuals compared to controls again revealed the overrepresentation of variants in the same gene. The variations discovered in the gene sequence are predicted to lead to a loss of function of the gene. NEK1 is known to have multiple roles in neurons, including maintenance of the cytoskeleton that gives the neuron its shape and promotes transport within the neuron. In addition, NEK1 has roles in regulating the membrane of the mitochondrion, which supplies energy to neurons, and in repairing DNA. Disruption of each of these functions through other means has been linked to increased risk of ALS.
Understanding the role of NEK1 in disease will provide an important new target for therapy development. The ALS Association is currently funding Landers and Catherine Lutz, PhD, senior research scientist at the Jackson Laboratories in Bar Harbour, Maine, to develop novel mouse models to better understand the consequences of the loss of the protein’s function for the ALS disease process. They will provide rapid access to these models for the broader ALS research community as soon as they are generated. These tools are important for ALS drug development.
UMass Medical School www.umassmed.edu/news/news-archives/2016/07/new-gene-variants-present-in-3-percent-of-all-als-patients/
