title: Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. tkwiatkowski@partners.org
authors.forename: T J
authors.initials: TJ
authors.lastname: Kwiatkowski
authors.forename: D A
authors.initials: DA
authors.lastname: Bosco
authors.forename: A L
authors.initials: AL
authors.lastname: Leclerc
authors.forename: E
authors.initials: E
authors.lastname: Tamrazian
authors.forename: C R
authors.initials: CR
authors.lastname: Vanderburg
authors.forename: C
authors.initials: C
authors.lastname: Russ
authors.forename: A
authors.initials: A
authors.lastname: Davis
authors.forename: J
authors.initials: J
authors.lastname: Gilchrist
authors.forename: E J
authors.initials: EJ
authors.lastname: Kasarskis
authors.forename: T
authors.initials: T
authors.lastname: Munsat
authors.forename: P
authors.initials: P
authors.lastname: Valdmanis
authors.forename: G A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: B A
authors.initials: BA
authors.lastname: Hosler
authors.forename: P
authors.initials: P
authors.lastname: Cortelli
authors.forename: P J
authors.initials: PJ
authors.lastname: de Jong
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshinaga
authors.forename: J L
authors.initials: JL
authors.lastname: Haines
authors.forename: M A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: J
authors.initials: J
authors.lastname: Yan
authors.forename: N
authors.initials: N
authors.lastname: Ticozzi
authors.forename: T
authors.initials: T
authors.lastname: Siddique
authors.forename: D
authors.initials: D
authors.lastname: McKenna-Yasek
authors.forename: P C
authors.initials: PC
authors.lastname: Sapp
authors.forename: H R
authors.initials: HR
authors.lastname: Horvitz
authors.forename: J E
authors.initials: JE
authors.lastname: Landers
authors.forename: R H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D017668:Age of Onset; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D012313:RNA / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013116:Spinal Cord / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D034702:RNA-Binding Protein FUS; D011993:Recombinant Fusion Proteins; D012313:RNA