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Department of Neurology

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Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics and Genomics | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology


Objective: Despite the strong genetic component of frontotemporal dementia (FTD), a substantial proportion of patients remain genetically unresolved. We performed an in-depth study of a family with an autosomal dominant form of FTD to investigate the underlying genetic cause.

Methods: Following clinical and pathologic characterization of the family, genetic studies included haplotype sharing analysis and exome sequencing. Subsequently, we performed immunohistochemistry, immunoblotting, and a microtubule repolymerization assay to investigate the potential impact of the candidate variant in tubulin alpha 4a (TUBA4A).

Results: The clinical presentation in this family is heterogeneous, including behavioral changes, parkinsonian features, and uncharacterized dementia. Neuropathologic examination of 2 patients revealed TAR DNA binding protein 43 (TDP-43) pathology with abundant dystrophic neurites and neuronal intranuclear inclusions, consistent with frontotemporal lobar degeneration-TDP type A. We identified a likely pathogenic variant in TUBA4A segregating with disease. TUBA4A encodes for alpha-tubulin, which is a major component of the microtubule network. Variants in TUBA4A have been suggested as a rare genetic cause of amyotrophic lateral sclerosis (ALS) and have sporadically been reported in patients with FTD without supporting genetic segregation. A decreased trend of TUBA4A protein abundance was observed in patients compared with controls, and a microtubule repolymerization assay demonstrated disrupted alpha-tubulin function. As opposed to variants found in ALS, TUBA4A variants associated with FTD appear more localized to the N-terminus, indicating different pathogenic mechanisms. Conclusions: Our findings support the role of TUBA4A variants as rare genetic cause of familial FTD.


frontotemporal dementia, genetics

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Copyright © 2021 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

DOI of Published Version



Mol MO, Wong TH, Melhem S, Basu S, Viscusi R, Galjart N, Rozemuller AJM, Fallini C, Landers JE, Kaat LD, Seelaar H, van Rooij JGJ, van Swieten JC. Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia. Neurol Genet. 2021 May 18;7(3):e596. doi: 10.1212/NXG.0000000000000596. PMID: 34169147; PMCID: PMC8221227. Link to article on publisher's site

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Neurology. Genetics

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Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.