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

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 o...

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Autores principales: Van Schoor, Evelien, Vandenbulcke, Mathieu, Bercier, Valérie, Vandenberghe, Rik, van der Zee, Julie, Van Broeckhoven, Christine, Otto, Markus, Hanseeuw, Bernard, Van Damme, Philip, Van Den Bosch, Ludo, Thal, Dietmar Rudolf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946841/
https://www.ncbi.nlm.nih.gov/pubmed/35327632
http://dx.doi.org/10.3390/biom12030440
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author Van Schoor, Evelien
Vandenbulcke, Mathieu
Bercier, Valérie
Vandenberghe, Rik
van der Zee, Julie
Van Broeckhoven, Christine
Otto, Markus
Hanseeuw, Bernard
Van Damme, Philip
Van Den Bosch, Ludo
Thal, Dietmar Rudolf
author_facet Van Schoor, Evelien
Vandenbulcke, Mathieu
Bercier, Valérie
Vandenberghe, Rik
van der Zee, Julie
Van Broeckhoven, Christine
Otto, Markus
Hanseeuw, Bernard
Van Damme, Philip
Van Den Bosch, Ludo
Thal, Dietmar Rudolf
author_sort Van Schoor, Evelien
collection PubMed
description 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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spelling pubmed-89468412022-03-25 Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology Van Schoor, Evelien Vandenbulcke, Mathieu Bercier, Valérie Vandenberghe, Rik van der Zee, Julie Van Broeckhoven, Christine Otto, Markus Hanseeuw, Bernard Van Damme, Philip Van Den Bosch, Ludo Thal, Dietmar Rudolf Biomolecules Article 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. MDPI 2022-03-12 /pmc/articles/PMC8946841/ /pubmed/35327632 http://dx.doi.org/10.3390/biom12030440 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Van Schoor, Evelien
Vandenbulcke, Mathieu
Bercier, Valérie
Vandenberghe, Rik
van der Zee, Julie
Van Broeckhoven, Christine
Otto, Markus
Hanseeuw, Bernard
Van Damme, Philip
Van Den Bosch, Ludo
Thal, Dietmar Rudolf
Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology
title Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology
title_full Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology
title_fullStr Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology
title_full_unstemmed Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology
title_short Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology
title_sort frontotemporal lobar degeneration case with an n-terminal tuba4a mutation exhibits reduced tuba4a levels in the brain and tdp-43 pathology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946841/
https://www.ncbi.nlm.nih.gov/pubmed/35327632
http://dx.doi.org/10.3390/biom12030440
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