Mutations in the gene for a protein called FUS may be a more widely distributed cause of amyotrophic lateral sclerosis (ALS) than previously recognized, according to three separate reports, all published in July 2010 in the journal Neurology.
The new results add to previous findings (see Mutations in FUS Gene Are a Cause of Familial ALS) and suggest mutations in the FUS gene, which plays a role in processing and transport of genetic information, may contribute to familial ALS (FALS) around the world. (The most common cause of FALS is any one of a large number of mutations in the gene for the SOD1 protein. However, 90 percent to 95 percent of ALS cases are not familial.)
The findings give scientists additional insights into the variety of factors that can contribute to the ALS disease process.
About the new findings
The new reports have found ALS-causing FUS mutations in U.S. FALS patients from a variety of ethnic backgrounds, as well as in patients with a juvenile-onset form of ALS in the United Kingdom, and people with FALS in Germany. The juvenile-onset ALS patients did not have a family history of the disease.
A group coordinated by Teepu Siddique at Northwestern University in Chicago found 17 FUS mutations in 22 U.S. families affected by FALS, two families affected by FALS with dementia (severe cognitive impairment), and one with FALS with Parkinson's disease and dementia.
The mutations were found in Americans of European origin, African-Americans, Latin Americans, and patients whose families came from China, Korea and Cambodia. "Although this study is not a population study, it suggests that FUS mutations may be a globally distributed genetic cause of FALS in patients of different genetic backgrounds," the researchers note in their paper, published online July 28, 2010, in Neurology.
Although MDA didn't fund this study, two directors of MDA/ALS Centers were part of the research team. Benjamin Brooks, who directs the MDA/ALS Center at Carolinas Medical Center in Charlotte, N.C., and W. King Engel, who directs the MDA/ALS Center at Good Samaritan Hospital in Los Angeles, were among the investigators.
German and Swiss study
Albert Ludolph at the University of Ulm in Germany coordinated researchers at his institution, at University Hospital of Zurich in Switzerland, and at Humboldt University in Berlin. This group, which published its findings online July 21, 2010, in Neurology, studied 133 German patients with nonfamilial ("sporadic") ALS and 58 with FALS that was not due to SOD1 mutations. They identified two FUS mutations in four German FALS families but no FUS mutations in the 133 sporadic ALS patients.
Olaf Ansorge at John Radcliffe Hospital in Oxford, United Kingdom, with colleagues at the University of Oxford and several other U.K. institutions, described their FUS findings online July 28, 2010, in Neurology.
This group conducted DNA analyses of three patients with so-called juvenile ALS, whose disease symptoms began between ages 17 and 22. None had a family history of the disease. Two of the patients were found to have the same mutation in the FUS gene, and the third had a different FUS gene mutation.
All three patients had abnormal clumps containing FUS protein in their nerve cells.
FUS protein molecules and molecules of another protein, TDP43, have previously been found in clumps in ALS-affected cells and are not always accompanied by mutations in the genes for these proteins. (See SOD1 Versus Other ALS: Apples and Oranges?)
Meaning for people with ALS
The findings are likely to shed additional light on the ALS disease process.
In an editorial accompanying the British study, neuropathologist David Munoz comments, "The history of medicine shows that careful dissection of disease mechanism is more likely to result in effective treatments than trying drugs on a whim."
Munoz, a professor of laboratory medicine and pathobiology at the University of Toronto, also notes that the absence of a family history can no longer be taken as an indication that ALS is not genetic. Some families may want to consider genetic testing even if only one family member has received an ALS diagnosis.
For more on ALS, FUS, TDP43 and related topics, see
Editor's note Aug. 16, 2010: A paper published online Aug. 10, 2010, in Human Molecular Genetics, describes how mutated FUS proteins that cause ALS form "stress granules" outside the cell nucleus in motor neurons. Stress granules indicate that the cell is under stress. It remains to be determined whether FUS-associated stress granules are linked to the formation of toxic clumps that occur in cells in end-stage ALS, or whether they are simply markers of altered cellular function that are not toxic in and of themselves. The stress granule study was coordinated by Lawrence Hayward and Daryl Bosco at the University of Massachusetts Medical School in Worcester.