SHORT COMMUNICATION The occurrence of mutations in FUS in a Belgian cohort of patients with familial ALS P. Van Damme a,b,c , A. Goris b , V. Race d , N. Hersmus b,c , B. Dubois a,b , L. Van Den Bosch b,c , G. Matthijs d and W. Robberecht a,b,c a Department of Neurology and b Department of Experimental Neurology, K.U. Leuven; c Vesalius Research Center, Flanders Institute of Biotechnology (VIB), Leuven; and d Laboratory for Molecular Diagnostics, Center for Human Genetics, K.U. Leuven, Belgium Keywords: amyotrophic lateral sclerosis, familial, FUS Received 27 July 2009 Accepted 02 October 2009 Background and purpose: Mutations in fused in sarcoma (FUS) were recently iden- tified as a cause of familial amyotrophic lateral sclerosis (ALS). The frequency of occurrence of mutations in FUS in sets of patients with familial ALS remains to be established. Methods: We sequenced the FUS gene in a cohort of patients with familial ALS seen at the neuromuscular clinic in Leuven. A total of 28 patients with SOD1-negative ALS from 22 families were analyzed. Results: We identified a R521H mutation in 4 patients, belonging to a kindred of dominantly inherited classical ALS. The mutation segregated with disease. Mutations in FUS were observed in 2.9% of ALS pedigrees in our cohort. Conclusions: These results show that mutations in FUS are also a significant cause of familial ALS in Belgium. Amyotrophic lateral sclerosis (ALS) is a neurodegen- erative disorder of motor neurons, in which a progres- sive paralysis and atrophy of muscles usually limits survival after disease onset to 2–5 years. In 10% of cases, it is an inherited disease. Mutations in the superoxide dismutase 1 (SOD1) gene are the most fre- quent genetic cause of ALS, responsible for 20%. In the majority of familial ALS cases, the underlying gene defect remains unknown. Recently, mutations in the gene FUS (fused in sarcoma)/TLS (translocated in liposarcoma) were discovered as a cause of ALS [1,2]. To date, 14 mutations have been identified in FUS. For five of them, clear segregation with the disease was shown. Most mutations are missense mutations in exon 14 or 15 and give rise to classical ALS, without cogni- tive decline. In the original studies, FUS mutations were found in about 3 to 5% of patients with familial ALS, but not in sporadic patients with ALS or healthy con- trols [1,2]. In an Italian study, two known FUS muta- tions have been observed in two different ALS families [3]. Mutations are inherited mostly in an autosomal dominant manner, except for the recessive mutation found in a family from Cape Verdean origin. The fre- quency of FUS mutations in other familial ALS pop- ulations remains unknown. Therefore, we sequenced FUS in a set of patients with SOD1-negative ALS from Belgian origin. Subjects and Methods Study population Between 1994 and 2008, DNA samples from patients with familial ALS seen at the neuromuscular clinic in Leuven were collected. Patients met the revised El Escorial criteria for diagnosis of ALS. Blood samples were obtained after informed consent, and this study was approved by the local ethical committee of the K.U. Leuven. Samples from a total of 82 patients with familial ALS, from 34 different families were collected. The FUS gene was investigated in 28 patients from 22 families in which no mutations in SOD1 [4,5], TDP-43 [6] or angiogenin were found. FUS analysis DNA was extracted from venous blood using standard methods. The 15 exons and exon–intron boundaries of FUS were amplified by PCR. To facilitate sequencing, Correspondence: P. Van Damme, Department of Neurology, Leuven University Hospital, Herestraat 49, 3000 Leuven, Belgium (tel.: +32 16 344280; fax: +32 16 344285; e-mail: philip.vandamme@ uz.kuleuven.be). All authors listed in this paper contributed to the experiments and revised the manuscript. 754 Ó 2009 The Author(s) Journal compilation Ó 2009 EFNS European Journal of Neurology 2010, 17: 754–756 doi:10.1111/j.1468-1331.2009.02859.x