title: TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations.
abstract: OBJECTIVE
  Increasing evidence suggests a direct role of the TAR DNA-binding protein 43 (TDP-43) in neurodegeneration. Mutations in the TARDBP gene, which codes for TDP-43, have been recently reported in familial and sporadic amyotrophic lateral sclerosis (ALS) cases.
  
  
  METHODS
  To further define the spectrum and frequency of TARDBP mutations, we present genetic analysis data on TARDBP in 314 ALS mainly Italian patients, including 16 subjects with non-SOD1 familial ALS.
  
  
  RESULTS
  We identified four heterozygous missense mutations in five unrelated ALS patients (1.6%). Two of these mutations (p.G348C and p.A382T) were detected in carriers coming from families with an autosomal dominant transmission of different geographic origin (Belgian and Italian, respectively). The Belgian pedigree showed several affected members within five generations and with variable clinical features. Two novel mutations (p.G294V and p.G295S) were identified in two sporadic cases.
  
  
  CONCLUSIONS
  The identification of five ALS patients carrying TARDBP alterations extends the spectrum of TARDBP mutations and supports the pathological role of TDP-43 in motor neurone disease. Our findings provide evidence that TARDBP mutations are not frequent in Italian sporadic ALS patients (1%); however, combined with the literature, our data further support TARDBP mutations as a relevant cause of familial ALS.
authors.affiliation: Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, Milan, Italy. roberto.delbo@unimi.it
authors.forename: R
authors.initials: R
authors.lastname: Del Bo
authors.forename: S
authors.initials: S
authors.lastname: Ghezzi
authors.forename: S
authors.initials: S
authors.lastname: Corti
authors.forename: M
authors.initials: M
authors.lastname: Pandolfo
authors.forename: M
authors.initials: M
authors.lastname: Ranieri
authors.forename: D
authors.initials: D
authors.lastname: Santoro
authors.forename: I
authors.initials: I
authors.lastname: Ghione
authors.forename: A
authors.initials: A
authors.lastname: Prelle
authors.forename: V
authors.initials: V
authors.lastname: Orsetti
authors.forename: M
authors.initials: M
authors.lastname: Mancuso
authors.forename: G
authors.initials: G
authors.lastname: Sorarù
authors.forename: C
authors.initials: C
authors.lastname: Briani
authors.forename: C
authors.initials: C
authors.lastname: Angelini
authors.forename: G
authors.initials: G
authors.lastname: Siciliano
authors.forename: N
authors.initials: N
authors.lastname: Bresolin
authors.forename: G P
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001483:Base Sequence / Q000235:genetics; D001530:Belgium; D025063:Chromosome Disorders / Q000235:genetics; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D007558:Italy; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree
chemical_list: D004268:DNA-Binding Proteins