Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia

Abstract

ObjectiveDespite 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.MethodsFollowing 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).ResultsThe 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.ConclusionsOur findings support the role of TUBA4A variants as rare genetic cause of familial FTD.

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

“…More recently, Mol et al, described another TUBA4A variant (R105C) in a family with different forms of dementia, among which bvFTD with prominent disinhibited behavior and parkinsonian-like gait disturbances [12]. One family member displayed unspecified dementia and comorbid Parkinsonism, and another relative was clinically diagnosed with Parkinson's disease.…”

“…Most of these mutations occur in the C-terminal end of the protein, which is important for its interaction with other tubulin subunits and associated proteins, such as kinesin [11]. More recently, however, mutations in the N-terminal region of TUBA4A were observed in patients with FTD without motor neuron disease [7,12]. In this report, we present the neuropathological post-mortem analysis of an FTD patient presenting with the semantic variant (svPPA) and an R64Gfs*90 TUBA4A mutation, and suggest reduction of TUBA4A protein levels as a potential pathogenic mechanism.…”

A Multiomics Profiling Based on Online Database Revealed Prognostic Biomarkers of BLCA

“…TUBA4A (tubulin alpha 4a) is the gene that encodes -tubulin. TUBA4A mutations have been linked to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [ 34 , 35 ]. Little articles concern TUBA4A in cancer, and only lung cancer was mentioned [ 36 – 38 ].…”

Bioinformatics and next generation sequencing data analysis to identify key genes and pathways influencing in Parkinson’s disease

“…SCN3B [405], PCDH19 [406], CNTNAP2 [407], STXBP1 [408], CHRNB2 [409], NAPA (NSF attachment protein alpha) [410], STX1B [411], GABRG2 [412], CAMKK2 [144], CNTNAP2 [413], ARHGEF9 [414], COX8A [415], CALHM1 [416], SLC45A1 [417], TLR5 [418] and KCNJ10 [419] could be acuseful prognostic biomarker in epilepsy. The altered expression of NPTX2 [420], VAMP2 [421], PRKAR1B [422], SNCB (synuclein beta) [199], AP2M1 [423], TUBA4A [424], KIF17 [425] and SYK (spleen associated tyrosine kinase) [426] might be related to the progression of dementia. The above evidence revealed that these genes were related with disorders of the nervous system and might have a function in PD.…”