A novel tau mutation in exon 9 (1260V) causes a four-repeat tauopathy

Grover, Andrew; England, Elisabet; Baker, Mary V.; Sahara, Naruhiko; Adamson, Jennifer; Granger, Brian; Houlden, Henry; Passant, Ulla; Yen, Shu Hui; DeTure, Michael; Hutton, Michael

doi:10.1016/s0014-4886(03)00393-5

Cited by 61 publications

(32 citation statements)

References 38 publications

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“…The most convincing MAPT mutation carrier with CBD pathology is a patient with an exon 9 mutation, p.I260V, who presented clinically with FTD and pathologically had a 4R tauopathy [15]. This p.I260V carrier had tau-immunoreactive astrocytic processes and argyrophilic thread-like lesions in white matter, yet swollen achromatic or ballooned neurons were absent.…”

Section: Discussionmentioning

confidence: 99%

Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration

et al. 2013

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In order to determine the frequency of microtubule associated protein tau gene (MAPT) mutations and rare variants in CBD, we performed a systematic sequence analysis of MAPT coding and 3′ untranslated region (3′UTR) in a large cohort of autopsy-confirmed CBD patients (N=109). This identified a novel MAPT mutation in exon 13, p.N410H, in a case that is neuropathologically indistinguishable from sporadic CBD. On immunoblot, the p.N410H mutation carrier had the same insoluble tau profile as seen in CBD. Additionally, tau expression analysis in brain tissue found a significant increase in the 4R/3R tau mRNA ratio (P=0.04), indicating that p.N410H disrupts tau isoform homeostasis. Biochemically, recombinant tau protein with p.N410H showed a marked increase in tau filament formation compared to wild-type tau (P<0.001), had a 19.2% decrease in rate of microtubule assembly (P<0.05), and a 10.3% reduction in the extent of total microtubule polymerization (P<0.01). Sequence analysis of the complete MAPT 3′UTR in autopsy-confirmed CBD cases further identified two rare variants with nominally significant association with CBD. An ATC nucleotide insertion (“MAPTv8”) was found in 4.6% of CBD patients compared to 1.2% of controls (P=0.031, OR=3.71), and rs186977284 in 4.6% CBD patients, but only 0.9% of controls (P=0.04, OR=3.58). Rs186977284 was also present in 2.7% of a large cohort of autopsy-confirmed PSP patients (N=566) and only 0.9% of an additional control series (P=0.034, OR=3.08), extending the association to PSP. Our findings show that mutations in MAPT can cause CBD and MAPT non-coding variants may increase the risk of complex 4R tauopathies.

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Section: Discussionmentioning

confidence: 99%

Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration

et al. 2013

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“…Furthermore, several TAU mutations are genetically linked to fronto-temporal dementia (FTD). [5][6][7][8][9][10][11][12] Tau expression is regulated by alternative splicing in a speciesspecific, developmental-and tissue-dependent manner. [13][14][15][16] Depending upon the inclusion or exclusion of exon 10, Tau isoforms with three or four microtubule binding domains are generated (3R and 4R, respectively).…”

Section: Introductionmentioning

confidence: 99%

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

et al. 2017

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TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by caspases at Aspartate 421 , to form a Tau metabolite known as δTau; δTau is increased in AD, due to the hyper-activation of caspases in AD brains. δTau is considered a critical toxic moiety underlying neurodegeneration, which initiates and facilitates NFT formation. As Tau is a therapeutic target in neurodegeneration, it is important to rigorously determine whether δTau is a toxic Tau species that should be pharmacologically attacked. To directly address these questions, we have generated a knock-in (KI) mouse called Tau DN -that expresses a Tau mutant that cannot be cleaved by caspases. Tau DN mice present short-term memory deficits and synaptic plasticity defects. Moreover, mice carrying two mutant Tau alleles show increased total insoluble hyper-phosphorylated Tau in the forebrain. These data are in contrast with the concept that δTau is a critical toxic moiety underlying neurodegeneration, and suggest that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic Tau species. Alternatively, it is possible that either a reduction or an increase in δTau leads to synaptic dysfunction, memory impairments and Tau pathology. Both possibilities will have to be considered when targeting caspase cleavage of Tau in AD therapy.

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“…An illustrative case showed a MAPT mutation (p.I260V) in exon 9 with differential FTD phenotype and CBD neuropathology (Grover et al 2003). …”

Section: Discussionmentioning

confidence: 99%

Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America

Gatto

Allegri

Prat

et al. 2017

Neurobiology of Aging

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Frontotemporal lobar degeneration (FTLD) is a neuropathological disorder that causes a variety of clinical syndromes including fronto-temporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). FTD associated with parkinsonism occurs frequently as a result of mutations in the C9orf72 gene and also in the genes coding for the protein associated with microtubule tau (MAPT) and progranulin (GRN) on chromosome 17 (FTDP-17). Herein we report an Argentinean family, of Basque ancestry, with an extensive family history of behavioral variant of FTD (bvFTD). Twenty one members over 6 generations composed the pedigree. An extensive neurological and neurocognitive examination was performed on 2 symptomatic individuals and 3 non-symptomatic individuals. Two different phenotypes were identified among affected members, CBS in the proband and FTD in his brother. DNA was extracted from blood for these five individuals and whole-exome sequencing (WES) was performed on 3 of them followed by Sanger sequencing of candidate genes on the other 2. In both affected individuals a missense mutation (p.P301L; rs63751273) in exon 10 of the MAPT gene (chr17q21.3) was identified. Among MAPT mutations, p.P301L is the most frequently associated to different phenotypes: a) aggressive, symmetrical and early-onset Parkinsonism; b) late parkinsonism associated with FTD and c) PSP but only exceptionally it is reported associated to CBS. This is the first report of the occurrence of the p.P301L-MAPT mutation in South America and supports the marked phenotypic heterogeneity among members of the same family as previously reported.

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A novel tau mutation in exon 9 (1260V) causes a four-repeat tauopathy

Cited by 61 publications

References 38 publications

Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration

Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America

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