TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations
Version of Record online: 19 FEB 2009
© 2009 The Author(s). Journal compilation © 2009 EFNS
European Journal of Neurology
Volume 16, Issue 6, pages 727–732, June 2009
How to Cite
Del Bo, R., Ghezzi, S., Corti, S., Pandolfo, M., Ranieri, M., Santoro, D., Ghione, I., Prelle, A., Orsetti, V., Mancuso, M., Sorarù, G., Briani, C., Angelini, C., Siciliano, G., Bresolin, N. and Comi, G. P. (2009), TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations. European Journal of Neurology, 16: 727–732. doi: 10.1111/j.1468-1331.2009.02574.x
- Issue online: 28 APR 2009
- Version of Record online: 19 FEB 2009
- Received 13 November 2008 Accepted 12 January 2009
- amyotrophic lateral sclerosis;
- missense mutation;
- motor neurone dysfunction;
- TARDBP gene;
Background and purpose: Increasing evidence suggests a direct role of the TAR DNA-binding protein 43 (TDP-43) in neurodegeneration. Mutations in the TARDBP gene, which codes for TDP-43, have been recently reported in familial and sporadic amyotrophic lateral sclerosis (ALS) cases.
Methods: To further define the spectrum and frequency of TARDBP mutations, we present genetic analysis data on TARDBP in 314 ALS mainly Italian patients, including 16 subjects with non-SOD1 familial ALS.
Results: We identified four heterozygous missense mutations in five unrelated ALS patients (1.6%). Two of these mutations (p.G348C and p.A382T) were detected in carriers coming from families with an autosomal dominant transmission of different geographic origin (Belgian and Italian, respectively). The Belgian pedigree showed several affected members within five generations and with variable clinical features. Two novel mutations (p.G294V and p.G295S) were identified in two sporadic cases.
Conclusion: The identification of five ALS patients carrying TARDBP alterations extends the spectrum of TARDBP mutations and supports the pathological role of TDP-43 in motor neurone disease. Our findings provide evidence that TARDBP mutations are not frequent in Italian sporadic ALS patients (1%); however, combined with the literature, our data further support TARDBP mutations as a relevant cause of familial ALS.