The existence of mutations that are causative of ALS in noncoding regions involved in autoregulation (Gitcho et al., 2009; Pesiridis et al., 2009) and the finding that one of these mutations shows increased TDP-43 transcript expression (Gitcho et al., 2009), strongly suggest that defects in self-regulation may result in disease. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.