Submission Details

TARDBP was first reported in autosomal dominant amyotrophic lateral sclerosis 10 (ALS) in 2008 (Sreedharan J, et al, 2008, PMID:18309045). Following the discovery of the TDP-43 protein as the principle component of ALS hallmark ubiquitinated protein inclusions within affected motor neurons (Neumann M, et al, 2006, PMID:17023659 and Arai T, et al 2006, PMID: 17084815), the authors investigated the TARDBP gene endoding this TDP-43 protein as a candidate gene in a cohort of index cases with familial ALS. Screening of TRADBP in this cohort identified missense mutation in a Caucasian family segregating with disease in a total of five affected family members across two generations. Genome-wide SNP-based linkage analysis including a total of 23 family members identified linkage to 1p36 with a parametric multipoint LOD score of 2.04. Fine mapping confirmed linkage with a maximal two-point LOD score of 2.73 at D1S450 and a highly significant multipoint lod score of 2.93. Extended cohort screening further identified a further two TARDBP missense mutations, each identified in a single sporadic ALS case. ALS is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. TARDBP encodes the TAR DNA binding protein 43 (TDP-43), and while the exact function of thise RNA/DNA protein is unknown, it is known to play roles in transcriptional repression and alternative splicing (PMID: 11470789). Evidence supporting this gene-disease relationship includes case-level data and experimental data. More than 60 mutations in TARDBP have been implicated in ALS, including single point mutations and small insertion/deletions, with the majority of these mutations falling in the final exon 6 of this gene (reviewed in PMID: 30837838, literature search in PMID: 32409511). A number of TDP-43 related phenotypes are reported among ALS patients, including its aggregation into protein inclusions, depletion in the nucleus and mislocalisation to the cytoplasm and sequestration into stress granules (reviewed in PMID: 30837838). Experimentally, this disease-gene relationship is also supported by a number of animal models that recapitulate various ALS related phenotypes. More genetic and experimental evidence is available in the literature, however the maximum score of 18pts has been reached. In summary TARDBP is definitively associated with autosomal dominant amyotrophic lateral sclerosis 10. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.