TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations
| Autor: | V. Orsetti, Corrado Angelini, Michelangelo Mancuso, D. Santoro, Alessandro Prelle, Massimo Pandolfo, Stefania Corti, Gianni Sorarù, R. Del Bo, Chiara Briani, Gabriele Siciliano, Isabella Ghione, Giacomo P. Comi, S. Ghezzi, Michela Ranieri, Nereo Bresolin |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
Heterozygote Genotype DNA Mutational Analysis Inheritance Patterns Mutation Missense Chromosome Disorders medicine.disease_cause TARDBP Genetic analysis Belgium medicine Humans Missense mutation Genetic Predisposition to Disease Genetic Testing Amyotrophic lateral sclerosis Aged Genes Dominant Genetic testing Genetics Mutation Base Sequence medicine.diagnostic_test business.industry Genetic Carrier Screening Amyotrophic Lateral Sclerosis Middle Aged medicine.disease Pedigree DNA-Binding Proteins Cross-Sectional Studies Italy Neurology Female Neurology (clinical) business Motor neurone disease |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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