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Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort

From the Department of Neurology (N.T., A.L.L., P.K., D.M.M.-Y., P.C.S., R.H.B., J.E.L.), University of Massachusetts Medical School, Worcester; Department of Neurology and Laboratory of Neuroscience (N.T., V.S., A.R.), Centro "Dino Ferrari," Università degli Studi di Milano-IRCCS Istituto Auxologico Italiano, Milan; Unit of Genetics of Neurodegenerative and Metabolic Diseases (C.G., F.T.), Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milan, Italy; Department of Neurology (T.J.K.), Massachusetts General Hospital, Boston; and Howard Hughes Medical Institute and Department of Biology (P.C.S.), Massachusetts Institute of Technology, Cambridge.

Address correspondence and reprint requests to Dr. John E. Landers, LRB604, 364 Plantation St., Worcester, MA 01605 john.landers{at}umassmed.edu

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.

Abbreviations: ALS = amyotrophic lateral sclerosis; FALS = familial amyotrophic lateral sclerosis; FTD = frontotemporal dementia; gDNA = genomic DNA; LMN = lower motor neuron; NLS = nuclear localization signal; UMN = upper motor neuron.

Editorial, page 1172

See also page 1176

Supplemental data at www.neurology.org

e-Pub ahead of print on September 9, 2009, at www.neurology.org.

Supported by the ALS Therapy Alliance, Project ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation, and the National Institute of Neurological Disorders and Stroke (NS050557 and NS050641). N.T., V.S., and A.R. were supported by the Italian Ministry of Health (Malattie Neurodegenerative, ex Art.56, n.533F/N1). F.T. and C.G. were supported by the Italian Ministry of Health grant RF2007/INN644440. P.S. was supported by the Howard Hughes Medical Institute (HHMI) through the auspices of Prof. H. Robert Horvitz, an Investigator in the HHMI. R.H.B. is a cofounder of AviTx, which targets development of therapies.

Disclosure: Author disclosures are provided at the end of the article.

Received March 19, 2009. Accepted in final form July 1, 2009.

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