Frontotemporal Lobar Degeneration Case with an N-Terminal Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology.

Recently, disease-associated variants of the gene were identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we present the neuropathological report of a patient with the semantic variant of primary progressive aphasia with a family history of Parkinsonism, harboring a novel frameshift mutation c.187del (p.Arg64Glyfs*90) in . Immunohistochemistry showed abundant TAR DNA-binding protein 43 kDa (TDP-43) dystrophic neurite pathology in the frontal and temporal cortex and the dentate gyrus of the hippocampus, consistent with frontotemporal lobar degeneration (FTLD). The observed pathology pattern fitted best with that of FTLD-TDP Type C. qPCR showed the presence of mutant mRNA. However, no truncated TUBA4A was detected at the protein level. A decrease in total mRNA and protein levels suggests loss-of-function as a potential pathogenic mechanism. This report strengthens the idea that N-terminal mutations are associated with FTLD-TDP. These N-terminal mutations possibly exert their pathogenic effects through haploinsufficiency, contrary to C-terminal mutations which are thought to disturb the microtubule network via a dominant-negative mechanism.