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Recently, mutations in TARDBP have been identified in sporadic amyotrophic lateral sclerosis (SALS), an adult onset motor neurodegenerative disorder, as well as in familial forms (FALS) of ALS.
Here we report an A to G (931 A>G) mutation in exon 6 of TARDBP, resulting in the substitution of methionine by valine at codon 311, in one patient with autosomal dominant FALS. This mutation was absent in 601 healthy controls (1202 chromosomes). Our data suggest a novel pathogenic missense mutation in exon 6 of TARDBP (M311V) causing ALS, confirming the aetiological role of the TAR DNA binding protein 43 (TDP-43) in the pathogenesis of motor neurodegeneration.
ALS is a motor neurodegenerative disease which is pathologically characterised by the selective loss of motor neurons in the motor cortex, brainstem and spinal cord.1 Furthermore, ubiquinated inclusions have been shown to be present in these motor neurons. TDP-43 was found to be a major component of these inclusions in ALS as well as in frontotemporal dementia (FTD). The exact pathogenic mechanism of TDP-43 has not yet been established but it is hypothesised that under pathological conditions TDP-43 is eliminated from the nuclei, resulting in decreased TDP-43 nuclear function.2
Approximately 5–10% of ALS cases are familial (FALS) of which 20% are caused by mutations in superoxide dismutase 1 (SOD1). The pathological findings lead to genetic screening of TARDBP in FTD …