Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia. (June 2021)

• Record Type: Journal Article
• Authors: Mol, Merel O.; Wong, Tsz H.; Melhem, Shamiram; Basu, Sreya; Viscusi, Riccardo; Galjart, Niels; Rozemuller, Annemieke J.M.; Fallini, Claudia; Landers, John E.; Kaat, Laura Donker; Seelaar, Harro; van Rooij, Jeroen G.J.; van Swieten, John C.
• Is Part Of: Neurology. Volume 7:Number 3(2021)
• Publication Date: 2021-06
• Subjects: Neurogenetics -- Periodicals; 616.80442
• DOI: 10.1212/NXG.0000000000000596
• Languages: English
• ISSNs: 2376-7839

Abstract

Abstract : 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 α-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 α-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.