Introduction

TAR-DNA-binding protein 43 (TDP-43) has recently been identified as the major pathological protein in abnormal inclusions in neurons and glial cells in sporadic amyotrophic lateral sclerosis (SALS) and SOD1 negative familial cases with amyotrophic lateral sclerosis (FALS). TDP-43 is evolutionarily conserved, consisting of two RNA recognition motifs and a glycine-rich C-terminal domain. It is involved in the regulation of expression and splicing, and in other cellular processes such as microRNA biogenesis, apoptosis and cell division.1 2

Starting in early 2008, dominant mutations in TARDBP gene have been reported by several groups as a primary cause of ALS. To date, a total of 30 mutations of TARDBP have been reported not only in SOD1-negative FALS cases (∼3%) but also in SALS cases (∼1.5%). All but one of the mutations identified (D169G) reside in exon 6 of the TARDBP gene, which encodes for the C-terminal glycine-rich domain of TDP-43. All of these mutations are dominantly inherited missense changes with the exception of a truncating mutation (Y374X) at the extreme C terminus of the protein.3

In this study, in order to investigate the presence and frequency of TARDBP mutations in a cohort of 310 south Italian patients affected by ALS, we performed a mutational screening of the exon 4 and exon 6 of the gene in SOD1-negative FALS and SALS patients. …