title: Enlarging clinical spectrum of FALS with TARDBP gene mutations: S393L variant in an Italian family showing phenotypic variability and relevance for genetic counselling.
abstract: OBJECTIVE
  The present study was aimed to enlarge the Italian ALS sample analysed for TARDBP gene mutations.
  
  
  METHODS
  Genomic DNA from 47 patients, 70 FTD patients and 158 controls was extracted from peripheral blood samples according to a standard protocol. The five coding exons (2-6) of the TARDBP gene and the flanking exon-intron boundaries were analysed by direct sequencing. Using ClustalW2 human TDP-43, protein sequence was aligned with TDP-43 protein sequence of different species.
  
  
  RESULTS
  A heterozygous c.1178 C-->T transition that leads to a change p.S393L was observed in a 75-years-old male patient and in his two affected siblings. A patient's brother had died at 69 years of age after a two-year history of ALS. In FTD patients no mutations were found.
  
  
  CONCLUSIONS
  We describe a further Italian family with FALS, in which a variant (p.S393L) of the TARDBP gene was identified. Clinical course and phenotypic variability in three affected siblings is presented and relevance for genetic counselling of patients and their families is underlined. At the present state of knowledge, we suggest that the same guidelines established for SOD1 molecular testing could be proposed also for TARDBP analysis in FALS.
authors.affiliation: Department of Oncology, Biology and Genetics, University of Genoa and U.O. Medical Genetics of Azienda Ospedaliera, Universitaria S. Martino di Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Origone
authors.forename: Claudia
authors.initials: C
authors.lastname: Caponnetto
authors.forename: Monica
authors.initials: M
authors.lastname: Bandettini Di Poggio
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ghiglione
authors.forename: Emilia
authors.initials: E
authors.lastname: Bellone
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ferrandes
authors.forename: Giovanni Luigi
authors.initials: GL
authors.lastname: Mancardi
authors.forename: Paola
authors.initials: P
authors.lastname: Mandich
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D005817:Genetic Counseling; D014644:Genetic Variation; D006801:Humans; D007438:Introns / Q000235:genetics; D007558:Italy; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C424710:HetF protein, Nostoc punctiforme