title: SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations.
abstract: BACKGROUND
  Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS).
  
  
  METHODS
  The relative contributions of the different mutations to ALS were estimated by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations.
  
  
  RESULTS
  31 pathogenic missense mutations were found in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harboured ANG variants. One family of Japanese origin with the P56S VAPB mutation was identified. Seven novel mutations (three in SOD1, two in TARDBP, two in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including five pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease onset than those presenting with a more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration.
  
  
  CONCLUSIONS
  This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.
authors.affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière INSERM UMR_S975, CNRS UMR7225, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, Paris, France. stephanie.millecamps@upmc.fr
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Millecamps
authors.forename: François
authors.initials: F
authors.lastname: Salachas
authors.forename: Cécile
authors.initials: C
authors.lastname: Cazeneuve
authors.forename: Paul
authors.initials: P
authors.lastname: Gordon
authors.forename: Bernard
authors.initials: B
authors.lastname: Bricka
authors.forename: Agnès
authors.initials: A
authors.lastname: Camuzat
authors.forename: Léna
authors.initials: L
authors.lastname: Guillot-Noël
authors.forename: Odile
authors.initials: O
authors.lastname: Russaouen
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bruneteau
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Pradat
authors.forename: Nadine
authors.initials: N
authors.lastname: Le Forestier
authors.forename: Nadia
authors.initials: N
authors.lastname: Vandenberghe
authors.forename: Véronique
authors.initials: V
authors.lastname: Danel-Brunaud
authors.forename: Nathalie
authors.initials: N
authors.lastname: Guy
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Lucette
authors.initials: L
authors.lastname: Lacomblez
authors.forename: Philippe
authors.initials: P
authors.lastname: Couratier
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: Danielle
authors.initials: D
authors.lastname: Seilhean
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.forename: Philippe
authors.initials: P
authors.lastname: Corcia
authors.forename: William
authors.initials: W
authors.lastname: Camu
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Guy
authors.initials: G
authors.lastname: Rouleau
authors.forename: Eric
authors.initials: E
authors.lastname: LeGuern
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
mesh_terms: D000328:Adult; D017677:Age Distribution; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008136:Longevity; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D012259:Ribonuclease, Pancreatic / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D013482:Superoxide Dismutase; C046366:angiogenin; D012259:Ribonuclease, Pancreatic