A genetic mutation in the gene for a protein called profilin 1 (PFN1) has been identified as a cause of familial amyotrophic lateral sclerosis (ALS), an MDA-supported team of researchers has reported.
Only about 5 percent of ALS is familial (where there is a history of ALS in more than one family member) with the other 95 percent occurring sporadically (without any family history of the disease).
Mutations in the PFN1 gene appear to cause familial ALS in 1 to 2 percent of people with the disease.
Located on chromosome 17, PFN1 codes for a protein that plays a key role in creating and remodeling the scaffolding — or cytoskeleton — in the muscle-controlling nerve cells called motor neurons.
The researchers note that their data add to a growing body of evidence that suggests cytoskeletal defects play a major role in motor neuron diseases.
The researchers studied two large families affected by ALS in which those with the disease did not have any known ALS-associated mutations. They found that each family carried a different mutation in the PFN1 gene.
Additional testing of samples taken from 272 people with familial ALS uncovered five occurrences of PFN1 mutations, including two that differed from those found in the first two families.
The researchers noted that the clinical course among people with PFN1-associated ALS includes age of onset at approximately 45 years, with symptoms appearing first in the arms and legs (limb onset).
The researchers found that the PFN1 protein readily assembles into protein clumps called aggregates (a hallmark of ALS).
Further tests were conducted to determine whether mutated PFN1 affects two other ALS-associated proteins — FUS and TDP43 — or the spinal muscular atrophy-related protein SMN. The team found no effects on the proper localization of FUS and SMN. But in approximately 30 to 40 percent of cells tested, PFN1 aggregates also contained TDP43, a result that suggests that mutated PFN1 may contribute to the ALS disease process by inducing the aggregation of TDP43.
The investigators also found that mutant PFN1 has negative effects on motor neurons — specifically on the long fibers called axons that carry signals to and from motor neurons in the brain and spinal cord. In cells carrying a PFN1 mutation, axons were shorter than those in cells that did not carry the mutation.
The multinational team of scientists, with members based in Canada, France, Israel, Italy, the Netherlands and the United States, published its findings online July 15, 2012, in Nature. (See Mutations in the Profilin 1 Gene Cause Familial Amyotrophic Lateral Sclerosis for the article abstract.)
The team was led by John Landers, associate professor of neurology, and Robert Brown, chair of neurology, both at the University of Massachusetts Medical School in Worcester. MDA supported Wilfried Rossoll for his contribution to this work. (Rossoll has a current MDA grant to study the biological role of the ALS disease protein TDP43.)