UNIPROT:P10636 - FACTA Search

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Query: UNIPROT:P10636 (tau protein)
5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Frontotemporal lobar degeneration (FTLD) encompasses a heterogeneous group of clinical syndromes that include frontotemporal dementia (FTD), frontotemporal dementia with motor neurone disease (FTD/MND), progressive non-fluent aphasia (PNFA), semantic dementia (SD) and progressive apraxia (PAX). Clinical phenotype is often assumed to be a poor predictor of underlying histopathology. Advances in immunohistochemistry provide the opportunity to re-examine this assumption. We classified pathological material from 79 FTLD brains, blind to clinical diagnosis, according to topography of brain atrophy and immunohistochemical characteristics. There were highly significant relationships to clinical syndrome. Atrophy was predominantly frontal and anterior temporal in FTD, frontal in FTD/MND, markedly asymmetric perisylvian in PNFA, asymmetric bitemporal in SD and premotor, parietal in PAX. Tau pathology was found in half of FTD and all PAX cases but in no FTD/MND or SD cases and only rarely in PNFA. FTD/MND, SD and PNFA cases were ubiquitin and TDP-43 positive. SD cases were associated with dystrophic neurites without neuronal cytoplasmic or intranuclear inclusions (FTLD-U, type 1), FTD/MND with numerous neuronal cytoplasmic inclusions (FTLD-U, type 2 ) and PNFA with neuronal cytoplasmic inclusions, dystrophic neurites and neuronal intranuclear inclusions (FTLD-U, type 3). MAPT mutations were linked to FTD and PGRN mutations to FTD and PNFA. The findings demonstrate predictable relationships between clinical phenotype and both topographical distribution of brain atrophy and immunohistochemical characteristics. The findings emphasise the importance of refined delineation of both clinical and pathological phenotype in furthering understanding of FTLD and its molecular substrate.
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PMID:Frontotemporal lobar degeneration: clinical and pathological relationships. 1756 65

Reported here is a new missense mutation V363I in exon 12 of the microtubule-associated protein tau (MAPT) gene associated with progressive nonfluent aphasia, with onset at the age of 69 years in a woman. Although near mute, she maintained complex activities and had no discernible deficits outside of language until the age of 75 years, when progressive gait and swallowing disturbances appeared. There was a history of late-onset aphasia and apraxia in her father. All of her children were asymptomatic adults, but psycholinguistic abnormalities were detected in those bearing the mutation, consisting of difficulties in comprehension, both reading (symbol discrimination and comprehension of oral spelling) and oral (matching sentences to pictures and comprehension of locative relationships). A mutation-bearing sibling showed no abnormalities at 70 years old, consistent with the limited penetrance expected in late-onset disease. The mutation, corresponding to a highly conserved residue in the fourth tubulin-binding repeat, was not present in 194 normal individuals with the same genetic background.
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PMID:Progressive nonfluent aphasia associated with a new mutation V363I in tau gene. 1771 60

Two hundred and twenty-three consecutive patients fulfilling clinical diagnostic criteria for frontotemporal lobar degeneration (FTLD), and 259 patients with motor neuron disease (MND), for whom genomic DNA was available, were investigated for the presence of mutations in tau (MAPT) and progranulin (PGRN) genes. All FTLD patients had undergone longitudinal neuropsychological and clinical assessment, and in 44 cases, the diagnosis had been pathologically confirmed at post-mortem. Six different PGRN mutations were found in 13 (6%) patients with FTLD. Four apparently unrelated patients shared exon Q415X 10 stop codon mutation. However, genotyping data revealed all four patients shared common alleles of 15 SNPs from rs708386 to rs5848, defining a 45.8-kb haplotype containing the whole PGRN gene, suggesting they are related. Three patients shared exon 11 R493X stop codon mutation. Four patients shared exon 10 V452WfsX38 frameshift mutation. Two of these patients were siblings, though not apparently related to the other patients who in turn appeared unrelated. One patient had exon 1 C31LfsX34 frameshift mutation, one had exon 4 Q130SfsX130 frameshift mutation and one had exon 10 Q468X stop codon mutation. In addition, two non-synonymous changes were detected: G168S change in exon 5 was found in a single patient, with no family history, who showed a mixed FTLD/MND picture and A324T change in exon 9 was found in two cases; one case of frontotemporal dementia (FTD) with a sister with FTD+MND and the other in a case of progressive non-fluent aphasia (PNFA) without any apparent family history. MAPT mutations were found in 17 (8%) patients. One patient bore exon 10 + 13 splice mutation, and 16 patients bore exon 10 + 16 splice mutation. When PGRN and MAPT mutation carriers were excluded, there were no significant differences in either the allele or genotype frequencies, or haplotype frequencies, between the FTLD cohort as a whole, or for any clinical diagnostic FTLD subgroup, and 286 controls or between MND cases and controls. However, possession of the A allele of SNP rs9897526, in intron 4 of PGRN, delayed mean age at onset by approximately 4 years. Patients with PGRN and MAPT mutations did not differ significantly from other FTLD cases in terms of gender distribution or total duration of illness. However, a family history of dementia in a first-degree relative was invariably present in MAPT cases, but not always so in PGRN cases. Onset of illness was earlier in MAPT cases compared to PGRN and other FTLD cases. PNFA, combined with limb apraxia was significantly more common in PGRN mutation cases than other FTLD cases. By contrast, the behavioural disorder of FTD combined with semantic impairment was a strong predictor of MAPT mutations. These findings complement recent clinico-pathological findings in suggesting identifiable associations between clinical phenotype and genotype in FTLD.
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PMID:Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations. 1819 87

Mutations in the progranulin gene (GRN) are a major cause of frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) but the distinguishing clinical and anatomical features of this subgroup remain unclear. In a large UK cohort we found five different frameshift and premature termination mutations likely to be causative of FTLD in 25 affected family members. A previously described 4-bp insertion mutation in GRN exon 2 comprised the majority of cases in our cohort (20/25), with four novel mutations being identified in the other five affected members. Additional novel missense changes were discovered, of uncertain pathogenicity, but deletion of the entire gene was not detected. The patient collection was investigated by a single tertiary referral centre and is enriched for familial early onset FTLD with a high proportion of patients undergoing neuropsychological testing, MRI and eventual neuropathological diagnosis. Age at onset was variable, but four mutation carriers presented in their 40s and when analysed as a group, the mean age at onset of disease in GRN mutation carriers was later than tau gene (MAPT) mutation carriers and duration of disease was shorter when compared with both MAPT and FTLD-U without mutation. The most common clinical presentation seen in GRN mutation carriers was behavioural variant FTLD with apathy as the dominant feature. However, many patients had language output impairment that was either a progressive non-fluent aphasia or decreased speech output consistent with a dynamic aphasia. Neurological and neuropsychological examination also suggests that parietal lobe dysfunction is a characteristic feature of GRN mutation and differentiates this group from other patients with FTLD. MR imaging showed evidence of strikingly asymmetrical atrophy with the frontal, temporal and parietal lobes all affected. Both right- and left-sided predominant atrophy was seen even within the same family. As a group, the GRN carriers showed more asymmetry than in other FTLD groups. All pathologically investigated cases showed extensive type 3 TDP-43-positive pathology, including frequent neuronal cytoplasmic inclusions, dystrophic neurites in both grey and white matter and also neuronal intranuclear inclusions. Finally, we confirmed a modifying effect of APOE-E4 genotype on clinical phenotype with a later onset in the GRN carriers suggesting that this gene has distinct phenotypic effects in different neurodegenerative diseases.
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PMID:A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. 1823 97

Mutations in the progranulin gene (PGRN) are a major cause of frontotemporal lobar degeneration (FTLD). Herein we estimated the contribution of the PGRN Leu271LeufsX10 mutation to FTLD and related disorders in the Brescia cohort. The PGRN Leu271LeufsX10 mutation was found in 31% of corticobasal syndrome (CBS), 29% of frontotemporal dementia with motorneuron disease (FTD-MND), 15% of behavioral variant frontotemporal dementia (FTD), 9.5% of primary progressive aphasia (PPA), 2% dementia with Lewy bodies and 0% of progressive supranuclear palsy and multiple system atrophy cases. The prevalence strongly increased in familial forms (75% CBS, 50% FTD-MND, 27% FTD, 18% PPA): in our cohort this mutation is a major disease determinant for FTLD-related disorders with a prominent motor component. MAPT haplotype was demonstrated to be a disease modifier in PGRN Leu271LeufsX10 carriers: in H1H2 subjects the disease onset was earlier than in H2H2 individuals. Sequencing of the whole PGRN gene disclosed a previously described mutation (c.2T>C, Met1X) and three novel ones (c.709-3; c.1011delG, His340ThrfsX21; c.1021C>T, Gln341X) in single families. In the Brescia cohort, while MAPT mutations have low prevalence, mutations in PGRN were shown in 28% of familial FTLD and 75% of familial CBS cases. The PGRN Leu271LeufsX10 mutation becomes one of the most common mutations worldwide, since it was identified in 38 patients belonging to 27 unrelated families.
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PMID:Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide. 1910 31

Frontotemporal dementia (FTD), characterized by neurodegeneration mainly in the frontal and temporal lobes, accounts for ca. 10-15% of all dementias. In 1892 the Czech-German neuropsychiatrist Arnold Pick reported the fi rst case of FTD in a 71-year-old patient suffering from progressive dementia, memory disturbances, and aphasia associated with frontal and temporal lobe atrophy and the presence of neuronal inclusions. Later the inclusions were named Pick bodies.The neuropathological hallmark of FTD is very differentiated. In contrast to Alzheimer's disease(AD), there are neither senile plaques nor neurofibrillary tangles in the brains of FTD patients.Frontotemporal dementias are tauopathies, a group of disorders caused by aberrant metabolism of tau protein, a family of proteins associated with microtubules (MAPT: macro-tubule-associated tau protein). In the nervous system the protein stabilizes microtubules in neuronal axons and is thus responsible for crucial processes in neuron metabolism, such as signal transduction, plasticity,and intracellular transport. In the human brain, six isoforms are produced from the MAPT gene (chromosome 17 q21.2) by alternative mRNA splicing. The isoforms differ in the number of amino acids in the protein chain, the presence of three (3R tau type) or four (4R tau type) domains responsible for binding to microtubules, and one or two inserts containing from 29 to 58 amino acids. The isoforms are modified posttranslationally by hyperphosphorylation, glycation,or oxidation, which can change the protein's properties and disturb its normal function. Altered metabolism of tau protein changes its interactions with tubulin, leading to destabilization of the microtubule structure and initiating the generation of toxic tau aggregates. The fi rst mutations in the MAPT gene responsible for frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) were found in 1998. So far over 40 mutations in the MAPT gene have been identified, mainly in families with autosomal dominant FTDP-17 but also in sporadic families with Pick's disease and AD. The known DNA changes have been classified according to their molecular effects into at least two groups: mutations that change the biochemical properties of tau protein and mutations that alter the alternative splicing of mRNA and lead very often to the overproduction of the 4R tau isoform. The imbalance in the ratio of the synthesized 3R and 4R tau isoforms stimulates protein aggregation and initiates neurodegeneration, leading to the development of dementia.
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PMID:[The genetics of dementias. Part 1: Molecular basis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)]. 1953 23

Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The neuropathology associated with most FTD is characterized by abnormal cellular aggregates of either transactive response DNA-binding protein with Mr 43 kDa (TDP-43) or tau protein. However, we recently described a subgroup of FTD patients, representing around 10%, with an unusual clinical phenotype and pathology characterized by frontotemporal lobar degeneration with neuronal inclusions composed of an unidentified ubiquitinated protein (atypical FTLD-U; aFTLD-U). All cases were sporadic and had early-onset FTD with severe progressive behavioural and personality changes in the absence of aphasia or significant motor features. Mutations in the fused in sarcoma (FUS) gene have recently been identified as a cause of familial amyotrophic lateral sclerosis, with these cases reported to have abnormal cellular accumulations of FUS protein. Because of the recognized clinical, genetic and pathological overlap between FTD and amyotrophic lateral sclerosis, we investigated whether FUS might also be the pathological protein in aFTLD-U. In all our aFTLD-U cases (n = 15), FUS immunohistochemistry labelled all the neuronal inclusions and also demonstrated previously unrecognized glial pathology. Immunoblot analysis of protein extracted from post-mortem aFTLD-U brain tissue demonstrated increased levels of insoluble FUS. No mutations in the FUS gene were identified in any of our patients. These findings suggest that FUS is the pathological protein in a significant subgroup of sporadic FTD and reinforce the concept that FTD and amyotrophic lateral sclerosis are closely related conditions.
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PMID:A new subtype of frontotemporal lobar degeneration with FUS pathology. 2069 41

Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. While the seminal cases were described at the turn of the 20th century, FTLD has only recently been appreciated as a leading cause of dementia, particularly in patients presenting before the age of 65 years. Three distinct clinical variants of FTLD have been described: (i) behavioural-variant frontotemporal dementia, characterized by changes in behaviour and personality in association with frontal-predominant cortical degeneration; (ii) semantic dementia, a syndrome of progressive loss of knowledge about words and objects associated with anterior temporal neuronal loss; and (iii) progressive nonfluent aphasia, characterized by effortful language output, loss of grammar and motor speech deficits in the setting of left perisylvian cortical atrophy. The majority of pathologies associated with FTLD clinical syndromes include either tau-positive (FTLD-TAU) or TAR DNA-binding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLD overlaps clinically and pathologically with the atypical parkinsonian disorders corticobasal degeneration and progressive supranuclear palsy, and with amyotrophic lateral sclerosis. The majority of familial FTLD cases are caused by mutations in the genes encoding microtubule-associated protein tau (leading to FTLD-TAU) or progranulin (leading to FTLD-TDP). The clinical and pathological heterogeneity of FTLD poses a significant diagnostic challenge, and in vivo prediction of underlying histopathology can be significantly improved by supplementing the clinical evaluation with genetic tests and emerging biological markers. Current pharmacotherapy for FTLD focuses on manipulating serotonergic or dopaminergic neurotransmitter systems to ameliorate behavioural or motor symptoms. However, recent advances in FTLD genetics and molecular pathology make the prospect of biologically driven, disease-specific therapies for FTLD seem closer than ever.
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PMID:Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. 2036 6

Frontotemporal dementia (FTD) is an important cause of non-Alzheimer's dementia and is the second most common cause of young onset dementia. FTD presents with progressive changes in behavior and personality (behavioral variant FTD) or language deficits (also known as primary progressive aphasia), although both commonly coexist. Patients with progressive aphasia are subclassified according to the pattern of language deficits into those with progressive non-fluent aphasia (PNFA) and semantic dementia (SD). FTD is pathologically heterogeneous, both macroscopically and on a molecular level, with tau positive, TDP-43 positive, and FUS positive intraneuronal inclusions recognized on immunohistochemical analysis. TDP-43 positive inclusions are also a feature of amyotrophic lateral sclerosis pathology, corroborating the observation of overlapping clinical features between the two conditions and reaffirming the FTD-ALS disease spectrum. Most FTD cases are sporadic, but an important minority is inherited in an autosomal dominant fashion, most commonly due to MAPT or progranulin gene mutations. Familial clusters of FTD and amyotrophic lateral sclerosis are also recognized but poorly understood. This paper reviews the clinical phenotypes, assessment and treatment of FTD in light of recent pathological and genetic discoveries.
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PMID:From FUS to Fibs: what's new in frontotemporal dementia? 2041 82

A 46-year-old woman who presented with prosopagnosia was clinically evaluated. Results of neuropsychological measures showed severe impairment in oral naming with anomia and a marked deficit in naming and recognition of famous faces. The clinical diagnosis was semantic dementia (SD). Genetic testing revealed a missense mutation V363I in exon 12 of the microtubule-associated protein tau (MAPT) gene. This is the description of an association between a mutation in the MAPT gene and a case of SD. The same mutation was recently described in a case of progressive non-fluent aphasia, but the prominent presenting feature in tau gene mutation cases is the behavioral variant of frontotemporal dementia, with typical symmetrical frontotemporal atrophy.
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PMID:Semantic dementia associated with mutation V363I in the tau gene. 2059 13

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