TARDBP and amyotrophic lateral sclerosis: Moreover, mutations in TARDBP, which account for ~4% of familial ALS cases, result in the pathogenic mislocalization of the TDP43 protein from the nucleus to the cytoplasm, causing defects in cytoplasmic-nuclear trafficking and reduced levels of proteins in the nucleus, such as the NHEJ factor XRCC4/LIG4 [114].