Abstract |
Recently, disease-associated variants of the TUBA4A 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 TUBA4A. 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 TUBA4A mRNA. However, no truncated TUBA4A was detected at the protein level. A decrease in total TUBA4A mRNA and protein levels suggests loss-of-function as a potential pathogenic mechanism. This report strengthens the idea that N-terminal TUBA4A mutations are associated with FTLD-TDP. These N-terminal mutations possibly exert their pathogenic effects through haploinsufficiency, contrary to C-terminal TUBA4A mutations which are thought to disturb the microtubule network via a dominant-negative mechanism.
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Authors | Evelien Van Schoor, Mathieu Vandenbulcke, Valérie Bercier, Rik Vandenberghe, Julie van der Zee, Christine Van Broeckhoven, Markus Otto, Bernard Hanseeuw, Philip Van Damme, Ludo Van Den Bosch, Dietmar Rudolf Thal |
Journal | Biomolecules
(Biomolecules)
Vol. 12
Issue 3
(03 12 2022)
ISSN: 2218-273X [Electronic] Switzerland |
PMID | 35327632
(Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- DNA-Binding Proteins
- RNA, Messenger
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Topics |
- Brain
(metabolism)
- DNA-Binding Proteins
(genetics, metabolism)
- Frontotemporal Dementia
- Frontotemporal Lobar Degeneration
(genetics, metabolism, pathology)
- Humans
- Mutation
- RNA, Messenger
(genetics)
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