Two independent research teams, one based in the United States and Canada and the other in the United Kingdom and Australia, have identified mutations in a gene called FUS on chromosome 16 as a cause of familial amyotrophic lateral sclerosis (ALS).
Both groups announced their findings in the Feb. 27, 2009, issue of the journal Science.
ALS is a disease in which muscle-controlling nerve cells in the brain and spinal cord (motor neurons) are lost, resulting in rapidly progressive paralysis and usually death within three to five years of symptom onset.
The disease is not familial (inherited) most of the time. The incidence of familial cases is thought to be 10 percent of all ALS cases, and 20 percent of the familial cases are due to mutations in a gene called SOD1.
Mutations in the newly implicated FUS gene are thought to account for some 3 percent to 5 percent of familial ALS cases, or 0.3 percent to 0.5 percent of all ALS cases.
Cellular and rodent models of ALS used in the laboratory to study the disease are, of necessity, familial disease models, since the cause of the nonfamilial (sporadic) form of the disease remains unknown and therefore can't be replicated. The identification of a new gene is likely to shed light on additional mechanisms underlying ALS, lead to the creation of new rodent models for the disease and may ultimately lead to identification of new therapeutic avenues.
The U.S. and Canadian team was coordinated by Thomas Kwiatkowski at Massachusetts General Hospital in Boston and Robert Brown, formerly at Mass General and now at the University of Massachusetts School of Medicine in Worcester. Brown was the director of the MDA/ALS Center at Mass General prior to his recent move to the University of Massachusetts and has received MDA funding for ALS research.
The team also included Guy Rouleau at the University of Montreal, the recipient of several MDA grants for research in ALS genetics.
The U.K. and Australian team was coordinated by Christopher Shaw at King's College London and the Institute of Psychiatry in London. First author Caroline Vance is also at both those institutions.
The North American group identified 13 mutations in the gene for the FUS protein in 17 familial ALS families. The U.K. and Australian group found three ALS-causing mutations in the FUS gene in nine families. Two of the mutations they identified were also found in the North American patients.
The FUS ("fused in sarcoma") protein is thought to be involved in DNA repair, the regulation of transcription from DNA to the related compound RNA, which becomes the genetic recipe for the synthesis of each protein; further RNA processing; and movement of RNA from the cell nucleus to the main part of the cell (the cytoplasm). Its name is derived from a previous identification of its role in a type of cancer called sarcoma.
Normally, FUS protein molecules stay in the nucleus and don't clump together. However, FUS protein molecules made from mutated FUS genes are more likely to be located in the cytoplasm, where they tend to clump together. This type of clumping (aggregation) has been correlated with degeneration of nerve cells in ALS and other conditions. In fact, the clumps are similar in appearance to those found in another rare form of familial ALS that's caused by mutations in the TDP 43 gene.
"Genes implicated in other motor neuron diseases also involve aspects of DNA and RNA metabolism," the authors of the U.S. and Canadian paper write. They note that "understanding the convergent pathophysiologies [shared adverse effects] of these genetic variants will provide insights into new targets for therapies for the motor neuron diseases."