High frequency ofTARDBPgene 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.

Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

“…Since it has also been published previously in controls, this substitution is likely to represent a non-pathogenic polymorphism (18,20,21). Novel synonymous SNPs were identified in 3 SALS cases in exon 2 (p.Leu27), exon 3 (p.Ser104) and exon 4 (p.Lys137), along with two SALS cases carrying the previously reported p.Ala66 SNP in exon 2 (18,21,23,(26)(27)(28).…”

“…All our patients had clinical features in keeping with ALS and no mutations were found in patients with a pure lower MN clinical The familial p.Met337Val mutation has been identified in three other families with MND (20,23,28). In FALS1 (Met337Val) a marked intrafamilial variation in disease duration was observed, ranging from 9 months to 17 years.…”

Novel TARDBP mutations in Nordic ALS patients

“…18 In the non-coding regions of TARDBP five genetic variations were detected, of which one (c.*208G4A) previously has been reported. 12 Segregation analyses were performed for c.*208G4A and c.543 þ 59A4G, and it suggested that neither is pathogenic.…”

“…This could be due to reduced penetrance of p.G357R, which is in agreement with other reported TARDBP mutations. [8][9][10][11][12]18 …”

“…This is within the range of what has been estimated in other ALS populations, 1-3%. [8][9][10][11][16][17][18][19] However, the ALS patients in our study were intentionally selected for a positive family history suggesting that mutations in TARDBP are rare in the Nordic ALS population.…”