title: Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene.
abstract: OBJECTIVE
  To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)-related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.
  
  
  METHODS
  Population-based, prospective cohort study.
  
  
  METHODS
  A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.
  
  
  METHODS
  Patients underwent mutational analysis for SOD1, FUS, and TARDBP.
  
  
  RESULTS
  Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144G>A (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94-single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness.
  
  
  CONCLUSIONS
  The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.
authors.affiliation: Department of Neuroscience, University of Torino, Via Cherasco 15, Turin, Italy. achio@usa.net
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borghero
authors.forename: Maura
authors.initials: M
authors.lastname: Pugliatti
authors.forename: Anna
authors.initials: A
authors.lastname: Ticca
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.forename: Cristina
authors.initials: C
authors.lastname: Moglia
authors.forename: Roberto
authors.initials: R
authors.lastname: Mutani
authors.forename: Maura
authors.initials: M
authors.lastname: Brunetti
authors.forename: Irene
authors.initials: I
authors.lastname: Ossola
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Marrosu
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Murru
authors.forename: Gianluca
authors.initials: G
authors.lastname: Floris
authors.forename: Antonino
authors.initials: A
authors.lastname: Cannas
authors.forename: Leslie D
authors.initials: LD
authors.lastname: Parish
authors.forename: Paola
authors.initials: P
authors.lastname: Cossu
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Abramzon
authors.forename: Janel O
authors.initials: JO
authors.lastname: Johnson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Sampath
authors.initials: S
authors.lastname: Arepalli
authors.forename: Sean
authors.initials: S
authors.lastname: Chong
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Gabriella
authors.initials: G
authors.lastname: Restagno
mesh_terms: D000368:Aged; D000409:Alanine; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology* / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D011446:Prospective Studies; D034702:RNA-Binding Protein FUS / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013912:Threonine
chemical_list: D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; D013912:Threonine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000409:Alanine