International team of researchers identifies mutations in the profilin 1 gene in several families of ALS patients
An international team of researchers, including Packard scientist Jonathan Glass and P2ALS researcher Bob Brown, has identified a new gene linked to inherited forms of ALS. Mutations in this gene, known as profilin 1, were initially identified in two families, and further genetic sequencing indicated that these mutations account for 1 to 2 percent of familial ALS cases. The study identifying this gene was published last week in the journal Nature.
“This study adds another piece to puzzle towards our understanding of the mechanisms of ALS pathogenesis,” said John Landers, a neuroscientist at the University of Massachusetts Medical School and lead author of the Nature study.
Landers and his colleagues had identified two large families with inherited ALS that didn’t have mutations in any of the other genes linked to ALS, including SOD1, TDP43, FUS, and the recently discovered C9ORF72. This indicated that a new, as yet undiscovered, mutation could be responsible for this cases. The scientists sequenced the exomes of the ALS patients, and compared these to the gene sequences found in general population. Although the exome is only a small portion of the overall genome, it contains the protein-coding regions of DNA where a majority of disease-causing mutations are located.
The researchers narrowed down the large number of harmless, naturally occurring genetic variations in every person’s exome by identifying mutations that only occurred in people with the disease and not in those without. Two mutations, both of them within the profilin 1 gene, were identified, one in each family. Further genetic sequencing of 272 additional familial ALS cases with unknown genetic mutations identified a total of four mutations in seven families. Landers says that mutations in profilin 1 account for 1 to 2 percent of inherited ALS cases.
Profilin 1 helps to build and strengthen the cytoskeleton, the cell’s internal support structure. The cytoskeleton helps proteins and other small molecules move around properly inside the cell, and it also helps give the cell the right shape for its job. When Landers and colleagues inserted the mutant profilin 1 gene into neurons grown in culture, they found that the neurons had shorter axons that grew in an abnormal fashion.
As well, cultured neurons containing mutant profilin 1 had large aggregates of this mutant protein in the cytoplasm. These aggregates also contained TDP43, a mutant protein also linked to familial ALS. The scientists still aren’t sure how mutations in profilin 1 cause disease, but they believe it may be due to toxicity from the clumps of protein, defects in the cytoskeleton of motor neurons, and/or abnormalities in motor neuron axons.
“We’re still trying to figure out why all of this is occurring, and how these changes lead to ALS,” Landers said. “This study shows that cytoskeletal defects can lead to ALS, and tell us that we should be looking closer at these pathways in the development of disease.”
# # #
100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.
Contributions are tax-deductible.
You may also be interested in visiting the RASCALS Store.
The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.