title: High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis.
abstract: Recent studies identified rare missense mutations in amyotrophic lateral sclerosis (ALS) patients in the TARDBP gene encoding TAR DNA binding protein (TDP)-43, the major protein of the ubiquitinated inclusions (UBIs) found in affected motor neurons (MNs). The aim of this study was to further define the spectrum of TARDBP mutations in a large cohort of 666 Italian ALS patients (125 familial and 541 sporadic cases). The entire coding region was sequenced in 281 patients, while in the remaining 385 cases only exon 6 was sequenced. In 18 patients, of which six are familial, we identified 12 different heterozygous missense mutations (nine novel) all locating to exon 6, which were absent in 771 matched controls. The c.1144G>A (p.A382T) variation was observed in seven patients, thus representing the most frequent TARDBP mutation in ALS. Analysis of microsatellites surrounding the TARDBP gene indicated that p.A382T was inherited from a common ancestor in 5 of the 7 patients. Altogether, the frequency of TARDBP gene mutations appears to be particularly high in Italian ALS patients compared to individuals of mainly Northern European origin (2.7% vs. 1%). Western blot analysis of lymphocyte extracts from two patients carrying the p.A382T and p.S393L TARDBP mutations showed the presence of lower molecular weight TDP-43 bands, which were more abundant than observed in healthy controls and patients negative for TARDBP mutations. In conclusion, this report contributes to the demonstration of the causative role of the TARDBP gene in ALS pathogenesis and indicates that mutations may affect the stability of the protein even in nonneuronal tissues.
authors.affiliation: Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy. lucia.corrado@med.unipmn.it
authors.forename: Lucia
authors.initials: L
authors.lastname: Corrado
authors.forename: A
authors.initials: A
authors.lastname: Ratti
authors.forename: C
authors.initials: C
authors.lastname: Gellera
authors.forename: E
authors.initials: E
authors.lastname: Buratti
authors.forename: B
authors.initials: B
authors.lastname: Castellotti
authors.forename: Y
authors.initials: Y
authors.lastname: Carlomagno
authors.forename: N
authors.initials: N
authors.lastname: Ticozzi
authors.forename: L
authors.initials: L
authors.lastname: Mazzini
authors.forename: L
authors.initials: L
authors.lastname: Testa
authors.forename: F
authors.initials: F
authors.lastname: Taroni
authors.forename: F E
authors.initials: FE
authors.lastname: Baralle
authors.forename: V
authors.initials: V
authors.lastname: Silani
authors.forename: S
authors.initials: S
authors.lastname: D'Alfonso
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D015153:Blotting, Western; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007558:Italy; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins