title: Fus gene mutations in familial and sporadic amyotrophic lateral sclerosis.
abstract: Mutations in the fused in sarcoma (FUS) gene have recently been found to cause familial amyotrophic lateral sclerosis (FALS). We screened FUS in a cohort of 200 ALS patients [32 FALS and 168 sporadic ALS (SALS)]. In one FALS proband, we identified a mutation (p.R521C) that was also present in her affected daughter. Their clinical phenotype was remarkably similar and atypical of classic ALS, with symmetric proximal pelvic and pectoral weakness. Distal weakness and upper motor neuron features only developed late. Neuropathological examination demonstrated FUS-immunoreactive neuronal and glial inclusions in the spinal cord and many extramotor regions, but no TDP-43 pathology. We also identified a novel mutation (p.G187S) in one SALS patient. Overall, FUS mutations accounted for 3% of our non-SOD1, non-TARDBP FALS cases and 0.6% of SALS. This study demonstrates that the phenotype with FUS mutations extends beyond classical ALS cases. Our findings suggest there are specific clinicogenetic correlations and provide the first detailed neuropathological description.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Heather
authors.initials: H
authors.lastname: Stewart
authors.forename: Mariely
authors.initials: M
authors.lastname: Dejesus-Hernandez
authors.forename: Charles
authors.initials: C
authors.lastname: Krieger
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.forename: Marife
authors.initials: M
authors.lastname: Fabros
authors.forename: Hannah
authors.initials: H
authors.lastname: Briemberg
authors.forename: Neil
authors.initials: N
authors.lastname: Cashman
authors.forename: Andrew
authors.initials: A
authors.lastname: Eisen
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology
chemical_list: D034702:RNA-Binding Protein FUS