TARDBP

TDP-43 (TAR DNA-binding protein 43) is a highly conserved, dosage-sensitive RNA-binding protein essential for RNA metabolism. It contains an N-terminal domain with a bipartite nuclear localization signal (NLS), two RNA recognition motifs (RRM1/RRM2) that bind UG-rich RNA and TG-rich ssDNA, and a glycine-rich C-terminal low-complexity domain (LCD) that mediates phase separation and harbors most ALS/FTD-associated mutations. TDP-43's core functions include: (1) repression of cryptic exon inclusion in pre-mRNAs such as STMN2 and UNC13A, (2) regulation of mRNA stability and transport including axonal transport of neurofilament mRNA, (3) autoregulation of its own mRNA levels via 3'-UTR binding, and (4) participation in stress granule dynamics through liquid-liquid phase separation. TDP-43 is predominantly nuclear but shuttles to the cytoplasm under stress. TDP-43 proteinopathy (nuclear depletion with cytoplasmic mislocalization and aggregation containing hyperphosphorylated, ubiquitinated, and C-terminally cleaved TDP-43) is present in 95-97% of ALS cases and approximately 45-50% of FTLD cases.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

• tdp43_proteinopathy via Amyotrophic Lateral Sclerosis named in the module itself