Objective: Mutations in the FUS gene on chromosome 16 have been recently discovered as a cause of familial amyotrophic lateral sclerosis (FALS). This study determined the frequency and identities of FUS gene mutations in a cohort of Italian patients with FALS.
Methods: We screened all 15 coding exons of FUS for mutations in 94 Italian patients with FALS.
Results: We identified 4 distinct missense mutations in 5 patients; 2 were novel. The mutations were not present in 376 healthy Italian controls and thus are likely to be pathogenic.
Conclusions: Our results demonstrate that FUS mutations cause 4% of familial amyotrophic lateral sclerosis cases in the Italian population.
Amyotrophic lateral sclerosis has a familial (fALS) presentation in about 10% of the cases. Since the discovery of SOD1 mutations, major progress has been made in the field and, so far, 28 loci have been found to be linked to fALS with 23 different genes in which mutations have been found.
In the year 2009, several groups have described mutations in a gene encoding FUS (fused in sarcoma), a nucleoprotein related to DNA and RNA metabolism[2, 3]. After these initial reports, confirmation of FUS involvement was given by the demonstration of mutations in two independent Italian kindreds. In two papers published back to back later in that year, further mutations were found in an Italian and in a French and French Canadian cohort. The paper on the Italian cohort is of particular interest, due to its size of 94 unrelated persons affected by ALS with a positive family history, defined as at least one affected relative within three generation. After systematically screening all 15 FUS exons, 4 mutations were found in 5 patients, providing accurate figures to compare the incidence of mutations in fALS. With 5 %, FUS comes to be a quite frequently involved gene, together with TARDBP (TDP-43) found in a similar proportion, SOD mutations being found in 20%. It was noted, that patients with FUS mutations had some unusual features, the report of additional cases will show, whether this is a specific feature in these patients. Interestingly, the mutations seem to cluster in some specific regions of the gene, including those encoding the glycine rich domain and the C-terminal.
These findings demonstrate the veracity of the argument made earlier that ALS is not to be considered as a single disease, but has variable underlying causes and presentations. While SOD mutations had pointed at a toxic metabolic pathogenesis, FUS, as well as TDP-43, are related in their functions in RNA binding and modulation. While the exact mechanism linking disturbed RNA handling to specific motoneuron degeneration and ALS clinical presentation is not yet clear, there is hope that these finding will advance our understanding of this disease and open new ways of therapy. Of course, the difficulties in transposition of findings in animal with SOD mutations to human with the disease are well known, but this may well be due to our previous focus on a single array of molecular events, due to the lack of knowledge of other. With the demonstration of mutations in FUS and other genes being involved in the disease, we certainly gain more insight in the complexity of neurodegeneration in ALS.
 Traub R, Mitsumoto H, Rowland LP. Research advances in amyotrophic lateral sclerosis, 2009 to 2010. Curr Neurol Neurosci Rep. 2011 11: 67-77.
 Kwiatkowski TJ, Jr., Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009 323: 1205-1208.
 Vance C, Rogelj B, Hortobagyi T, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 323: 1208-1211.
 Chio A, Restagno G, Brunetti M, et al. Two Italian kindreds with familial amyotrophic lateral sclerosis due to FUS mutation. Neurobiol Aging. 2009 30: 1272-1275.
 Ticozzi N, Silani V, LeClerc AL, et al. Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort. Neurology. 2009 73: 1180-1185.
 Belzil VV, Valdmanis PN, Dion PA, et al. Mutations in FUS cause FALS and SALS in French and French Canadian populations. Neurology. 2009 73: 1176-1179.
Jean-Marc Burgunder is Professor of Neurology at the University of Bern, Switzerland and Chairman of the EFNS Scientist Panel on Genetic and Metabolic Disorders