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dc.contributor.authorMol, Merel O.
dc.contributor.authorWong, Tsz H.
dc.contributor.authorMelhem, Shamiram
dc.contributor.authorBasu, Sreya
dc.contributor.authorViscusi, Riccardo
dc.contributor.authorGaljart, Niels
dc.contributor.authorRozemuller, Annemieke J. M.
dc.contributor.authorFallini, Claudia
dc.contributor.authorLanders, John E.
dc.contributor.authorKaat, Laura Donker
dc.contributor.authorSeelaar, Harro
dc.contributor.authorvan Rooij, Jeroen G. J.
dc.contributor.authorvan Swieten, John C.
dc.date2022-08-11T08:10:00.000
dc.date.accessioned2022-08-23T16:51:56Z
dc.date.available2022-08-23T16:51:56Z
dc.date.issued2021-05-18
dc.date.submitted2021-10-04
dc.identifier.citation<p>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 <em>TUBA4A</em> Variant Associated With Familial Frontotemporal Dementia. Neurol Genet. 2021 May 18;7(3):e596. doi: 10.1212/NXG.0000000000000596. PMID: 34169147; PMCID: PMC8221227. <a href="https://doi.org/10.1212/NXG.0000000000000596">Link to article on publisher's site</a></p>
dc.identifier.issn2376-7839 (Linking)
dc.identifier.doi10.1212/NXG.0000000000000596
dc.identifier.pmid34169147
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41953
dc.description.abstractObjective: 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=34169147&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © 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.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectfrontotemporal dementia
dc.subjectgenetics
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectGenetics and Genomics
dc.subjectMolecular and Cellular Neuroscience
dc.subjectNervous System Diseases
dc.subjectNeurology
dc.titleNovel TUBA4A Variant Associated With Familial Frontotemporal Dementia
dc.typeJournal Article
dc.source.journaltitleNeurology. Genetics
dc.source.volume7
dc.source.issue3
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5791&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4758
dc.identifier.contextkey25262253
refterms.dateFOA2022-08-23T16:51:56Z
html.description.abstract<p>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.</p> <p>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).</p> <p>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.</p>
dc.identifier.submissionpathoapubs/4758
dc.contributor.departmentDepartment of Neurology
dc.source.pagese596


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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.
Except where otherwise noted, this item's license is described as 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.