Genetic variants in the promoter of TARDBP in sporadic amyotrophic lateral sclerosis.

All patients with sporadic amyotrophic lateral sclerosis (SALS) have TDP-43 inclusions in their motor neurons, suggesting this protein plays a major role in the disease. Coding mutations in the gene for TDP-43, TARDBP, have been found in only a few patients with SALS. However, the non-coding regulatory regions of TARDBP have not yet been examined in SALS. We therefore sequenced both coding and non-coding regions of TARDBP in 46 tissue-banked SALS brains (brain DNA was used to detect somatic mutations). Non-coding variants (in the promoter or intron 1) were detected in 16 patients (35%) and coding variants in 4 (9%). Two known promoter variants were found more frequently in SALS patients than in controls. Two other variants, found in one patient each but not in controls, have potential regulatory functions. In addition, a novel exon 2 change with predicted functional effects was found in one patient. In summary, variants in the promoter and other non-coding regions of TARDBP may disturb the regulation of this gene in some patients with SALS.