Alternative titles; symbols
HGNC Approved Gene Symbol: MAPT
SNOMEDCT: 230270009; ICD10CM: G31.0, G31.01; ICD9CM: 331.1, 331.11;
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:45,894,554-46,028,334 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | {Parkinson disease, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 |
| Dementia, frontotemporal, with or without parkinsonism | 600274 | Autosomal dominant | 3 | |
| Pick disease | 172700 | Autosomal dominant | 3 | |
| Supranuclear palsy, progressive | 601104 | Autosomal dominant | 3 | |
| Supranuclear palsy, progressive atypical | 260540 | Autosomal recessive | 3 |
The microtubule-associated proteins (MAPs) coassemble with tubulin (see 602529) into microtubules in vitro. Microtubule-associated protein tau appears to be enriched in axons. Neve et al. (1986) identified tau cDNA clones in a human fetal brain cDNA library. The clones recognized a 6-kb message that was expressed in human brain but not in other human tissues and exhibited a developmental shift in size.
By screening cDNA libraries prepared from the frontal cortex of an Alzheimer disease patient and from fetal human brain, Goedert et al. (1988) isolated the cDNA for a core protein of the paired helical filament of Alzheimer disease (AD; 104300). The partial amino acid sequence of this core protein was used to design synthetic oligonucleotide probes. The cDNA encodes a protein of 352 amino acids that contains a characteristic amino acid repeat in its carboxyl-terminal half. Because of extensive homology to the sequence of the mouse microtubule-associated protein tau, they stated that this protein must constitute the human equivalent of mouse tau. Tau protein mRNA was found in normal amounts in the frontal cortex from patients with Alzheimer disease.
Goedert et al. (1989) determined the sequences of 6 tau isoforms produced in adult human brain by alternative mRNA splicing. The proteins are composed of 352 to 441 amino acids. The isoforms differ from each other by the presence or absence of 29-amino acid or 58-amino acid inserts located in the N terminus and a 31-amino repeat located in the C terminus. Inclusion of the latter, which is encoded by exon 10 of the tau gene, gives rise to the 3 tau isoforms with 4 repeats each; the other 3 isoforms have 3 repeats each. Normal cerebral cortex contains similar levels of 3-repeat and 4-repeat tau isoforms. The repeats and some adjoining sequences constitute the microtubule-binding domains of tau (see also Hutton et al., 1998).
Holzer et al. (2004) determined that the longest form (441 amino acids) of the chimpanzee brain tau protein shares 100% amino acid identity with human tau. The nonconstitutively spliced exon 4A differed at 3 of 251 amino acid positions. Identities for gorilla and gibbon tau with human tau were 99.5% and 99.0%, respectively. Analysis of 8 polymorphic markers revealed that the nonhuman primates had a higher prevalence of the H2 haplotype, in contrast to humans, in whom the H1 haplotype is more common. Holzer et al. (2004) noted that chimpanzee brains show resistance to developing tau pathology and suggested that differences in intronic sequences of the tau gene may be responsible.
Andreadis et al. (1992) found that the tau isoforms that predominate in human brain are encoded by 11 exons.
Conrad et al. (2002) identified an intronless gene, saitohin (STH; 607067), located in the intron between exons 9 and 10 of the tau gene.
The MAPT gene was assigned to chromosome 17 by hybridization of a cDNA clone to flow-sorted and spot-blotted chromosomes (Neve et al., 1986) and to 17q21 by in situ hybridization (Donlon et al., 1987).
In the course of constructing a radiation hybrid map of the breast cancer (113705) region of 17q, Abel et al. (1993) concluded that the tau protein gene (symbolized MTBT1 by them) is proximal to GP3A (173470), located at 17q21.32, and distal to TOP2A (126430) and THRA1 (190120), located at 17q11.2. ERBB2 (164870), previously localized to 17q21-q22, was found to be proximal to all of these. Poorkaj et al. (2001) identified and sequenced a human PAC and a mouse BAC containing the entire MAPT and Mtapt genes, respectively. They found that the corticotropin-releasing hormone receptor gene (CRHR1; 122561) is the next gene 5-prime to MAPT. The gene located 3-prime to MAPT and encoded by the opposite DNA strand has a predicted sequence identical to the KIAA1267 cDNA (KANSL1; 612452) identified from adult human brain by Nagase et al. (1999).
Alonso et al. (1996) reported studies on the microtubule-associated protein tau in Alzheimer disease. They noted that in the brains of patients with Alzheimer disease the neuronal cytoskeleton is progressively disrupted and replaced by tangles of paired helical filaments (PHFs), and that PHFs are composed mainly of hyperphosphorylated forms of tau (called 'AD P-tau' by them). They demonstrated that in solution normal tau associated with the hyperphosphorylated AD P-tau to form large tangles of filaments. They also demonstrated that dephosphorylation with alkaline phosphatase abolished the ability of AD P-tau to aggregate in vitro.
Hypothesizing that restoring the function of phosphorylated tau might prevent or reverse PHF formation in Alzheimer disease, and with the knowledge that PIN1 (601052) specifically isomerizes phosphorylation of a serine or threonine that precedes proline and regulates the function of mitotic phosphoproteins, Lu et al. (1999) demonstrated that the WW domain of PIN1 binds to phosphorylated tau at threonine-231 (T231). The T231 residue is hyperphosphorylated in Alzheimer disease and is phosphorylated to a certain extent in the normal brain. Using a pull-down assay, Lu et al. (1999) demonstrated that PIN1 binds to hyperphosphorylated tau from the brains of people with Alzheimer disease but not to tau from age-matched healthy brains. By immunoblotting, Lu et al. (1999) detected endogenous PIN1 in the PHFs of diseased brains, and using immunohistochemistry, they found that recombinant PIN1 binds to pathologic tau. Using immunohistochemistry, Lu et al. (1999) localized PIN1 to the nucleus in healthy brains. In the brains of people with Alzheimer disease, PIN1 staining was associated with pathologic tau in neuronal cells. Lu et al. (1999) also demonstrated that phosphorylated tau could neither bind microtubules nor promote microtubule assembly. However, PIN1 was able to restore the ability of phosphorylated tau to bind microtubules and promoted microtubule assembly in vitro. The level of soluble PIN1 in the brains of Alzheimer patients was greatly reduced compared to that in age-matched control brains. The authors concluded with the hypothesis that since depletion of PIN1 induces mitotic arrest and apoptotic cell death, sequestration of PIN1 into PHFs may contribute to neuronal death.
Schneider et al. (1999) presented evidence that challenged the common hypothesis that hyperphosphorylated tau promotes aggregation into PHFs. Using an in vitro system, they showed that treatment with several different kinases phosphorylated tau and caused detachment from microtubules, yet at the same time protected against the formation of PHFs. The authors suggested the findings are due most likely to the complex interaction of tau's ability to adopt many conformations and the presence of phosphorylation sites with differing affinities and locations.
Senile plaques and neurofibrillary tangles, the 2 hallmark lesions of Alzheimer disease, are the result of the pathologic deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar beta-amyloid peptide; neurofibrillary tangles represent intracellular bundles of self-assembled hyperphosphorylated tau proteins. These 2 lesions are often present in the same brain areas, and Rapoport et al. (2002) presented work that suggested a mechanistic link between them. They analyzed whether tau plays a key role in fibrillar beta-amyloid-induced neurite degeneration in central nervous system neurons. Cultured hippocampal neurons obtained from wildtype, tau knockout, and human tau transgenic mice were treated with fibrillar amyloid-beta. Morphologic analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of amyloid-beta. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of amyloid-beta.
From detailed analysis of pathologic load and spatiotemporal distribution of beta-amyloid deposits and tau pathology in sporadic Alzheimer disease, Delacourte et al. (2002) concluded that there is a synergetic effect of amyloid aggregation in the propagation of tau pathology.
The association of intronic mutations in the MAPT gene (e.g., 157140.0004) in frontotemporal dementia with parkinsonism (600274) highlights the involvement of aberrant pre-mRNA splicing in the pathogenesis of neurodegenerative disorders. To establish a model system for studying the role of pre-mRNA splicing in neurodegenerative diseases, Jiang et al. (2000) constructed a MAPT minigene that reproduced alternative splicing in both cultured cells and in vitro biochemical assays. They demonstrated that mutations in a nonconserved intronic region of the human MAPT gene led to increased splicing between exons 10 and 11. Systematic biochemical analyses indicated the importance of U1 snRNP (180740) and, to a lesser extent, U6 snRNP (180692) in differentially recognizing wildtype versus intron-mutant MAPT pre-mRNAs.
Goode et al. (2000) analyzed the structure and function of the 3-repeat (3R) and 4-repeat (4R) tau isoforms. Rather than having linear, sequentially arranged tubulin-binding domains, the isoforms have specific core microtubule-binding domains that lead to complex intramolecular folding interactions. Flanking regions were also found to contribute to the binding activity in the 3-repeat isoform, but less so in the 4-repeat isoform. Goode et al. (2000) suggested that the 2 isoforms form distinct structures that likely have different functional capabilities. Panda et al. (2003) noted that the abnormally high ratio of 4R to 3R tau in the MAPT gene might lead to neuronal cell death by altering normal tau functions in adult neurons. They tested whether 3R and 4R tau might differentially modulate the dynamic instability of microtubules in vitro using video microscopy. Although both isoforms promoted microtubule polymerization and decreased the tubulin critical subunit concentration to approximately similar extents, 4R tau stabilized microtubules significantly more strongly than 3R tau. Panda et al. (2003) suggested a 'dosage effect' or haploinsufficiency model in which both tau alleles must be active and properly regulated to produce appropriate amounts of each tau isoform to maintain microtubule dynamics within a tolerable window of activity.
Stamer et al. (2002) showed that elevated levels of tau inhibit intracellular transport in neurons, particularly the plus-end-directed transport by kinesin motors from the center of the cell body to the neuronal processes. This inhibition is significant because critical organelles, such as peroxisomes, mitochondria, and transport vesicles carrying supplies for the growth cone, are unable to penetrate the neurites, leading to stunted growth, increased susceptibility to oxidative stress, and likely pathologic aggregation of proteins such as amyloid precursor protein (APP; 104760). Stamer et al. (2002) concluded that the tau:tubulin ratio is normally low, and that increased levels of tau become detrimental to the cell.
Giasson et al. (2003) showed that alpha-synuclein (SNCA; 163890) induces fibrillization of tau, and that coincubation of alpha-synuclein and tau synergistically promotes fibrillization of both proteins in vitro. In vivo studies of mice with an alpha-synuclein mutation or a tau mutation showed filamentous inclusions of both proteins, which are abundant neuronal proteins that normally adopt an unfolded conformation but polymerize into amyloid fibrils in disease. The findings suggested an interaction between alpha-synuclein and tau that drives the formation of pathologic inclusions in human neurodegenerative diseases.
Rizzu et al. (2004) presented evidence suggesting that DJ1 (602533) colocalizes within a subset of pathologic tau inclusions in tauopathies, and that the solubility of DJ1 is altered in association with its aggregation within these inclusions.
Petrucelli et al. (2004) reported that CHIP (607207), a ubiquitin ligase that interacts directly with Hsp70/90 (140550/140571), induced ubiquitination and increased aggregation of tau. Tau lesions in human postmortem tissue were immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor-1 (HSF1; 140580) led to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 showed a significant reduction in tau levels. The authors concluded that the Hsp70/CHIP chaperone system may play an important role in the regulation of tau turnover and the selective elimination of abnormal tau species.
Liu et al. (2004) investigated the mechanisms leading to abnormal hyperphosphorylation of tau in pathologic states. They demonstrated that human brain tau was modified by O-GlcNAcylation, a type of protein O-glycosylation by which the monosaccharide beta-N-acetylglucosamine (GlcNAc) attaches to serine/threonine residues via an O-linked glycosidic bond. This glycosylation regulated tau phosphorylation in a site-specific manner both in vitro and in vivo. At most of the phosphorylation sites, the process negatively regulated tau phosphorylation. In an animal model of starved mice, low glucose uptake/metabolism that mimicked those observed in Alzheimer disease brain produced a decrease in O-GlcNAcylation and consequent hyperphosphorylation of tau at the majority of the phosphorylation sites. The O-GlcNAcylation level in Alzheimer disease brain extracts was decreased as compared to that in controls.
Using Western blotting, immunoprecipitation assays, and surface plasmon resonance analysis, Guo et al. (2006) showed that beta-amyloid-40 and -42 formed stable complexes with soluble tau and that prior phosphorylation of tau inhibited complex formation. Immunostaining of brain extracts from patients with AD and controls showed that phosphorylated tau and beta-amyloid were present within the same neuron. Guo et al. (2006) postulated that an initial step in AD pathogenesis may be the intracellular binding of soluble beta-amyloid to soluble nonphosphorylated tau.
In studies of rodent and human cells, Li et al. (2007) found that overexpression of hyperphosphorylated tau antagonized apoptosis of neuronal cells by stabilizing beta-catenin (CTNNB1; 116806). The findings explained why NFT-bearing neurons survive proapoptotic insults and instead die chronically of degeneration.
Roberson et al. (2007) found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human APP, without altering their high A-beta levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Roberson et al. (2007) concluded that thus, tau reduction can block A-beta- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer disease and related conditions.
To determine the effects of tau on dynein (600112) and kinesin (602809) motility, Dixit et al. (2008) conducted single-molecule studies of motor proteins moving along tau-decorated microtubules. Dynein tended to reverse direction, whereas kinesin tended to detach at patches of bound tau. Kinesin was inhibited at about a tenth of the tau concentration that inhibited dynein, and the microtubule-binding domain of tau was sufficient to inhibit motor activity. The differential modulation of dynein and kinesin motility suggested that microtubule-associated proteins (MAPs) can spatially regulate the balance of microtubule-dependent axonal transport.
De Calignon et al. (2010) used in vivo multiphoton imaging to observe tangles and activation of executioner caspases in living tau transgenic mice (Tg4510 strain) created by SantaCruz et al. (2005), and found that caspase activation occurs prior to tangle formation and precedes tangle formation by hours to days. New tangles form within a day. After a new tangle forms, the neuron remains alive and caspase activity seems to be suppressed. Similarly, introduction of wildtype 4-repeat tau (tau-4R) into wildtype animals triggered caspase activation, tau truncation, and tau aggregation. Adeno-associated virus-mediated expression of a construct mimicking caspase-cleaved tau into wildtype mice led to the appearance of intracellular aggregates, tangle-related conformational- and phospho-epitopes, and the recruitment of full-length endogenous tau to the aggregates. On the basis of these data, de Calignon et al. (2010) proposed a new model in which caspase activation cleaves tau to initiate tangle formation, then truncated tau recruits normal tau to misfold and form tangles. Because tangle-bearing neurons are long-lived, de Calignon et al. (2010) suggested that tangles are 'off pathway' to acute neuronal death. De Calignon et al. (2010) suggested that soluble tau species, rather than fibrillar tau, may be the critical toxic moiety underlying neurodegeneration.
Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-beta (104760) are strongly associated with Alzheimer disease, are more toxic than amyloid-beta(1-42) and amyloid-beta(1-40), and have been proposed as initiators of Alzheimer disease pathogenesis. Nussbaum et al. (2012) reported a mechanism by which pE-amyloid-beta may trigger Alzheimer disease. Amyloid-beta-3(pE)-42 co-oligomerizes with excess amyloid-beta(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from amyloid-beta(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% amyloid-beta-3(pE)-42 plus 95% amyloid-beta(1-42) (5% pE-amyloid-beta) seed new cytotoxic LNOs through multiple serial dilutions into amyloid-beta(1-42) monomers in the absence of additional amyloid-beta-3(pE)-42. LNOs isolated from human Alzheimer disease brain contained amyloid-beta-3(pE)-42, and enhanced amyloid-beta-3(pE)-42 formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. Nussbaum et al. (2012) concluded that amyloid-beta-3(pE)-42 confers tau-dependent neuronal death and causes template-induced misfolding of amyloid-beta(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Nussbaum et al. (2012) concluded that their results raised the possibility that amyloid-beta-3(pE)-42 acts similarly at a primary step in Alzheimer disease pathogenesis.
Using in situ hybridization and immunohistochemical analyses, Lund et al. (2013) showed that TTBK1 (619415) was a neuron-specific kinase in human brain, with primary expression in the somatodendritic compartment. TTBK1 phosphorylated tau at ser422 and colocalized with phosphorylated ser422 pretangle neurons, but not with late-stage neurofibrillary tangles.
Kondo et al. (2015) investigated how traumatic brain injury (TBI), an environmental risk factor for Alzheimer disease, leads to tauopathy. Kondo et al. (2015) found robust cis phosphorylated tau protein (P-tau) pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produced cis P-tau, which disrupted axonal microtubule networks and mitochondrial transport, spread to other neurons, and led to apoptosis. This process, which they termed 'cistauosis,' appears long before other tauopathy. Treating TBI mice with cis antibody blocked cistauosis, prevented tauopathy development and spread, and restored many TBI-related structural and functional sequelae. Thus, Kondo et al. (2015) concluded that cis P-tau is a major early driver of disease after TBI and leads to tauopathy in traumatic encephalopathy and Alzheimer disease. The authors suggested that the cis antibody may be further developed to detect and treat TBI and prevent progressive neurodegeneration after injury.
Faraco et al. (2019) reported that dietary salt induced hyperphosphorylation of tau followed by cognitive dysfunction in mice, and that these effects were prevented by restoring endothelial nitric oxide production. The nitric oxide deficiency reduced neuronal calpain (see 114220) nitrosylation and resulted in enzyme activation, which, in turn, led to tau phosphorylation by activating cyclin-dependent kinase-5 (CDK5; 123831). Salt-induced cognitive impairment was not observed in tau-null mice or in mice treated with anti-tau antibodies, despite persistent cerebral hypoperfusion and neurovascular dysfunction. Faraco et al. (2019) concluded that these findings identified a causal link between dietary salt, endothelial dysfunction, and tau pathology, independent of hemodynamic insufficiency. They further suggested that avoidance of excessive salt intake and maintenance of vascular health may help to stave off the vascular and neurodegenerative pathologies that underlie dementia in the elderly.
Rauch et al. (2020) showed that the low density lipoprotein receptor-related protein-1 (LRP1; 107770) controls the endocytosis of tau and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Rauch et al. (2020) concluded that their results identified LRP1 as a key regulator of tau spread in the brain.
Cryoelectron Microscopy
Using cryoelectron microscopy, Falcon et al. (2018) determined the structures of tau filaments from patients with Pick disease (172700), a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues lys254-phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer disease. Falcon et al. (2018) concluded that their findings showed how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.
Using cryoelectron microscopy, Falcon et al. (2019) determined the structure of tau filaments from the brains of 3 individuals with chronic traumatic encephalopathy (CTE) at resolutions down to 2.3 angstroms. Falcon et al. (2019) showed that filament structures were identical in the 3 cases but were distinct from those of Alzheimer disease and Pick disease, and from those formed in vitro. Similar to Alzheimer disease, all 6 brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of 3-repeat tau and S305-R379 of 4-repeat tau form the ordered core of 2 identical C-shaped protofilaments. However, a different conformation of the beta-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer disease. Falcon et al. (2019) concluded that their structures provided a unifying neuropathologic criterion for CTE, and supported the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.
Using cryoelectron microscopy, Zhang et al. (2020) analyzed the structures of tau filaments extracted from the brains of 3 individuals with corticobasal degeneration (CBD). These filaments were identical between cases, but distinct from those seen in Alzheimer disease (104300), Pick disease (172700), and chronic traumatic encephalopathy. The core of a CBD filament comprises residues lysine-274 to glutamate-380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3, and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen 4-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine-370 from the sequence after R4.
The MAPT gene has a polymorphic inversion resulting in 2 main haplotypes: the H1 haplotype, which comprises the more common human noninverted sequence, and the H2 haplotype, which comprises an inverted sequence and includes several other genes within its 900-kb extent (review by Donnelly et al., 2010). The promoter in H1 chromosomes is more efficient at driving transcription than the promoter sequence on the H2 haplotype (Kwok et al., 2004).
Studies by Baker et al. (1999), Skipper et al. (2004), and others identified extensive linkage disequilibrium in the 17q21.31 region and considerable divergence between the H1 and H2 lineages of MAPT. Using a refined physical map of chromosome 17q21.31, Stefansson et al. (2005) uncovered a 900-kb inversion polymorphism in this region accounting for these observations. Chromosomes with the inverted segment in different orientations represent the 2 distinct lineages H1 and H2 that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians, but is found at a rate of approximately 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. The frequency is about 6% in Africans and less than 1% in East Asians. Stefansson et al. (2005) showed that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.
Zody et al. (2008) used comparative sequencing approaches to investigate the evolutionary history of the European-enriched 17q21.31 MAPT inversion polymorphism. The authors presented a detailed BAC-based sequence assembly of the inverted human H2 haplotype and compared it to the sequence structure and genetic variation of the corresponding 1.5-Mb region for the noninverted H1 human haplotype and that of chimpanzee and orangutan. Zody et al. (2008) found that the inversion of the MAPT region is similarly polymorphic in other great ape species, and presented evidence that the inversions occurred independently in chimpanzees and humans. In humans, the inversion breakpoints correspond to core duplications with the LRRC37 gene family (see 616555). The analysis of Zody et al. (2008) favored the H2 configuration and sequence haplotype as the likely great ape and human ancestral state, with inversion recurrences during primate evolution. The authors further showed that the H2 architecture has evolved more extensive sequence homology, perhaps explaining its tendency to undergo microdeletion associated with mental retardation in European populations.
Donnelly et al. (2010) genotyped SNPs in the MAPT gene corresponding to the H1 and H2 haplotypes in 3,135 individuals from 66 populations worldwide. The H2 inversion was found at the highest frequencies in Southwest Asia and Southern Europe (approximately 30%). Elsewhere in Europe, the frequency of H2 varied from less than 5% in Finns to 28% in Orcadians. The H2 inversion haplotype occurs at low frequencies (1 to 10%) in Africa, Central Asia, East Asia, and the Americas, although the East Asian and Amerindian alleles may be due to recent gene flow from Europe. Molecular evolution analyses indicated that the H2 haplotype originally arose in Africa or Southwest Asia. The most recent common human ancestor was estimated to be from 13,600 to 108,400 years ago, which is much more recent than the 3 million year age estimated by Stefansson et al. (2005).
Rademakers et al. (2004) reported that in the previous 5 years, research had identified 34 different pathogenic MAPT mutations in 101 families worldwide. They described the considerable differences in clinical and pathologic presentation of patients with MAPT mutations and summarized the effect of the different mutations on tau functioning. In addition, they discussed the role of tau as a genetic susceptibility factor, together with the genetic evidence for additional causal genes for tau-positive as well tau-negative dementia.
Frontotemporal Dementia with Parkinsonism
In 13 families with autosomal dominant frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP17; 600274), Hutton et al. (1998) identified mutations in the MAPT gene: 3 were missense mutations (157140.0001-157140.0003) and 3 were mutations in the 5-prime splice site of exon 10 (157140.0004-157140.0006). All of the splice site mutations destabilized a potential stem-loop structure likely involved in regulating the alternative splicing of exon 10 (Goedert et al., 1989), resulting in more frequent usage of the 5-prime splice site and an increased proportion of tau transcripts that included exon 10. The increase in exon 10+ mRNA was expected to increase the proportion of tau containing 4 microtubule-binding repeats, consistent with the neuropathology described in families with FTDP17. Most cases showed neuronal and/or glial inclusions that stained positively with antibodies raised against tau, although the tau pathology varied considerably in both its quantity and characteristics; the disorder is one of several termed 'tauopathies.'
Varani et al. (1999) determined the 3-dimensional structure of the tau exon 10 splicing regulatory element RNA by means of NMR spectroscopy. They showed that it does indeed form a stable, folded stem-loop structure whose thermodynamic stability is reduced by FTDP17 mutations and increased by compensatory mutations. By exon trapping, Varani et al. (1999) showed that the reduction in thermodynamic stability was correlated with increased splicing of exon 10.
Hong et al. (1998) indicated that more than 10 exonic and intronic mutations of the MAPT gene had been identified in about 20 FTDP17 families. Analyses of soluble and insoluble tau proteins from brains of FTDP17 patients indicated that different pathogenic mutations differentially altered distinct biochemical properties and stoichiometry of brain tau isoforms. Functional assays of recombinant tau proteins with different FTDP17 missense mutations implicated all but 1 of these mutations in disease pathogenesis by reducing the ability of tau to bind microtubules and promote microtubule assembly.
In a study of frontotemporal dementia in the Netherlands from January 1994 to June 1998, Rizzu et al. (1999) found 37 patients who had one or more first-degree relatives with dementia. A mutation in the MAPT gene was found in 17.8% of the group of patients with FTDP17 and in 43% of patients with FTDP17 who also had a positive family history of the disorder. Three distinct missense mutations, G272V (157140.0002), P301L (157140.0001), and R406W (157140.0003) accounted for 15.6% of the mutations. The missense mutations and a single amino acid deletion that was detected in 1 patient, strongly reduced the ability of tau to promote microtubule assembly. Rizzu et al. (1999) suggested that the MAPT mutations cause disturbances in the interactions of the tau protein with microtubules, resulting in hyperphosphorylation of tau protein, assembly into filaments, and subsequent cell death.
Verpillat et al. (2002) found that the tau H1/H1 genotype (see below) was significantly overrepresented in 100 patients with frontotemporal dementia compared to controls (odds ratio for H1/H1 = 1.95). In addition, there was a significant negative effect in carriers of both the H1/H1 genotype and the APOE2 allele (107741).
Goedert et al. (1998) reviewed the role of tau mutations in frontotemporal dementias. Heutink (2000) reviewed the role of tau protein in frontotemporal dementia and other neurodegenerative disorders. Hutton (2001) reviewed the known missense and splice site mutations in the tau gene that are associated with disease and described different mechanisms involved in pathogenesis, including disruption of the interaction between tau and tubulin, deposition of abnormal tau filaments, and the generation of abnormal ratios of tau isoforms.
Using purified recombinant proteins, Alonso et al. (2004) showed that several FTDP17-associated tau missense mutations made tau a more favorable substrate for abnormal hyperphosphorylation compared with wildtype tau. Both the phosphorylation kinetics, due to induced conformational changes, and the phosphorylation stoichiometry, due to increased phosphorylation of more than a single site, were more favorable in the mutant proteins. The mutant proteins polymerized into filaments more readily than wildtype tau, leading to decreased ability to bind wildtype tau.
Progressive Supranuclear Palsy
Conrad et al. (1997) demonstrated an association between progressive supranuclear palsy (PSNP; 601104) and a dinucleotide TG repeat polymorphism in intron 9 of the MAPT gene. They demonstrated overrepresentation of the most common allele (a0) and genotype (a0/a0) in PSNP. Baker et al. (1999) identified a series of polymorphisms scattered throughout the MAPT gene and described 2 extended haplotypes, designated H1 and H2, that cover the entire gene. The dinucleotide TG polymorphism alleles a0 (11 repeats), a1 (12 repeats), and a2 (13 repeats) are inherited with the H1 haplotype, whereas the a3 (14 repeats) and a4 (15 repeats) alleles are inherited with the H2 haplotype. In a total of approximately 200 unrelated Caucasian individuals, there was complete disequilibrium between polymorphisms that spanned the gene, suggesting that the establishment of the 2 haplotypes was an ancient event and that either recombination was suppressed in this region, or recombinant genes were selected against. Baker et al. (1999) showed that the more common haplotype, designated H1, was significantly overrepresented in patients with progressive supranuclear palsy, extending earlier reports of the association between the intronic dinucleotide polymorphism allele a0 and the disorder.
Litvan et al. (2001) examined 63 patients with PSNP and found that the presence of the tau H1/H1 genotype was significantly greater in patients compared to controls. There was no difference between PSNP cases with one H1 or two H1 alleles in the age of onset, severity, or survival of patients, thus showing that tau genotyping does not predict the prognosis of PSNP. However, Litvan et al. (2001) noted that most of the PSNP patients carried the H1/H1 genotype (88.9%) and none of the patients carried the H2/H2 genotype, thus limiting the conclusions of the study.
Using single-nucleotide polymorphisms, Pittman et al. (2004) mapped linkage disequilibrium (LD) in the regions flanking MAPT and established the maximum extent of the haplotype block on chromosome 17q21.31 as a region covering approximately 2 Mb. The gene-rich region extended centromerically beyond the corticotropin-releasing hormone receptor-1 gene (CRHR1; 122561) to a region of approximately 400 kb, where there was a complete loss of LD. The telomeric end was defined by an approximately 150-kb region just beyond the WNT3 (165330) gene. The authors showed that the entire, fully extended H1 haplotype was associated with PSNP, which implicates several other genes in addition to MAPT as candidate pathogenic loci.
Rademakers et al. (2005) and Pittman et al. (2005) used a large collection of pathologically confirmed PSNP samples to fine map PSNP risk on H1 chromosomes in PSNP cases and controls. PSNP risk was associated with an extended subhaplotype (H1c), and the risk for PSNP was narrowed to a 22-kb region in intron 0 of MAPT by examining younger patients with, presumably, a larger genetic component to their disease. The most likely explanation of the association of the MAPT H1 haplotype and PSNP is that variants in the H1 (and H2) haplotypes confer risk of (protect against) disease by altering expression at the locus, with the risky H1 haplotype expressing higher levels of MAPT.
Kwok et al. (2008) showed that the MAPT G-to-A allele of rs242557, which partially defines the H1c subhaplotype, results in increased MAPT gene expression.
Pick Disease
Zhukareva et al. (2002) used biochemical, immunohistochemical, and ultrastructural methods to characterize pathologic tau isoform composition in 14 sporadic Pick disease (172700) brains. They found that both 3R and 4R microtubule-binding isoforms were present in gray and white matter of various brain regions, particularly the cortex and hippocampus. Specifically, 7 cases had predominantly pathologic 3R isoforms, 4 cases had a mixture of 3R and 4R isoforms, and 3 cases had primarily 4R isoforms. Isolated tau filaments were primarily straight, but twisted forms were also present. Although the cases shared similar clinical and neuropathologic features, the biochemical profiles of abnormal tau were diverse.
Parkinson Disease
In a large study of 1,056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, Martin et al. (2001) found that haplotypes of single-nucleotide polymorphisms (SNPs) yielded strong evidence of association with late-onset Parkinson disease (PD; 168600). Positive association was found with 1 haplotype (P = 0.009) and a negative association with another haplotype (P = 0.007). The results were thought to implicate MAPT as a susceptibility gene for idiopathic Parkinson disease.
Kwok et al. (2004) identified several SNPs in the MAPT promoter region corresponding to the H1 and H2 haplotypes, as well as a novel variant of the H1 haplotype, termed H1-prime. In a cohort of 206 patients with idiopathic late-onset Parkinson disease, the authors found a significant association with the H1/H1 promoter genotype. In vitro analysis showed that the H1 haplotype was more efficient at driving gene expression than the H2 haplotype, suggesting that increased MAPT expression is a susceptibility factor in idiopathic PD.
Alternate mRNA splicing of exons 2, 3, and 10 of the MAPT gene results in the expression of 6 polypeptides in the human CNS (Higuchi et al., 2002). The predominant isoforms differ by the presence of either 3 or 4 microtubule-binding domains, the 3-repeat (3R) and 4-repeat (4R) isoforms, which result from the exclusion or inclusion of exon 10 (Panda et al., 2003). Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP17; 600274) is called, in pathology terms, a '4R tauopathy' because of the presence of fibrillar aggregates comprising the 4R tau isoform. There are 2 predominant MAPT haplotypes--termed H1 and H2 and extending more than 500 kb--in which variants appear to be in complete linkage disequilibrium; H1 and H2 haplotypes do not recombine (Pastor et al., 2002). H1/H1 homozygous genotypes are overrepresented in 4R tauopathies. Using H1-specific SNPs, Skipper et al. (2004) demonstrated that MAPT H1 is a misnomer and consists of a family of recombining H1 alleles. Population genetics, linkage disequilibrium, and association analyses showed that specific MAPT H1 subhaplotypes are preferentially associated with Parkinson disease. Using a sliding scale of MAPT H1-specific haplotypes in age- and sex-matched PD cases and controls from central Norway, Skipper et al. (2004) refined the disease association to within an interval of approximately 90 kb of the 5-prime end of the MAPT locus.
In a study of 557 PD patient-control pairs, Mamah et al. (2005) found that individuals with the SNCA Rep1 261/261 or MAPT H1/H1 genotypes had an increased risk of PD compared to those with neither genotype (odds ratio of 1.96); however, the combined effect of the 2 genotypes was the same as for either genotype alone. Mamah et al. (2005) suggested that the MAPT H1/H1 genotype may cause increased SNCA fibrillization in persons with lower SNCA protein concentrations due to genotypes other than Rep1 261/261. In persons with the Rep1 261/261 genotype, the MAPT H1/H1 genotype confers no additional risk because the SNCA protein is already at threshold concentration for self-fibrillization.
Kwok et al. (2005) identified 2 functional SNPs in the GSK3B (605004) gene that influenced its transcriptional activity and correlated with enhanced phosphorylation of MAPT in vitro, respectively. Conditional logistic regression analysis of the genotypes of 302 Caucasian PD patients and 184 Chinese PD patients found an association between the GSK3B polymorphisms, MAPT haplotype, and risk of PD. Kwok et al. (2005) concluded that GSK3B polymorphisms interact with MAPT haplotypes to modify disease risk in PD. Garcia-Gorostiaga et al. (2009) confirmed the findings of Kwok et al. (2005) in a cohort of 314 Spanish patients with PD.
Among 1,762 PD patients, Zabetian et al. (2007) found a significant association between the H1/H1 genotype and risk of disease (odds ratio of 1.46; p = 8 x 10(-7)). The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. Within H1/H1 individuals, there was no association with H1 subhaplotypes.
Among 659 PD patients, Goris et al. (2007) found a synergistic interaction between the MAPT H1 haplotype and an A-to-G SNP (rs356219) in the 3-prime region of the SNCA gene. Carrying the combination of risk genotypes at both loci approximately doubled the risk of disease (p = 3 x 10(-6)). The findings suggested that MAPT and SNCA are involved in shared or converging pathogenic pathways and may have a synergistic effect. Cognitive decline and the development of dementia was associated with the H1/H1 genotype (p = 10(-4)). In a final analysis that combined data from other studies, Goris et al. (2007) confirmed the association of the H1/H1 genotype with PD (odds ratio of 1.4; p = 2 x 10(-19)).
In a study of 543 PD patients from 296 families with a proband and at least 1 affected first-degree relative as part of the GenePD Study group, Tobin et al. (2008) found a significant association between the H1 haplotype and PD (odds ratio of 1.72; p = 0.0008). In particular, rs1800547 of the H1 haplotype was significantly associated with PD (p = 0.02 after Bonferroni correction). Tobin et al. (2008) also identified a novel H1 subhaplotype that predicted an even greater increased risk for PD (OR, 4.48; p = 0.003), but some of these SNPs extended beyond the 3-prime region of MAPT. The expression of 4R MAPT, STH (607067), and KIAA1267 was significantly increased in cerebellum samples from PD patients relative to controls. No difference in expression was observed for 3R repeat MAPT. The findings suggested that variations in MAPT gene expression may underlie the association with PD.
Among 202 Spanish patients with PD, Seto-Salvia et al. (2011) found a significant association between the H1 haplotype and the development of dementia (odds ratio of 3.73, p = 0.002). Examination of subhaplotypes showed that a rare version of H1, named H1p, was overrepresented in PD patients with dementia compared to controls (2.3% vs 0.1%, p = 0.003). There was a protective effect for the H2a haplotype on PD with dementia. There was no association between MAPT variants and disease among 164 patients with Alzheimer disease or 41 with Lewy body dementia.
In a statistical analysis of 5,302 PD patients and 4,161 controls from 15 sites, Elbaz et al. (2011) found no evidence for an interactive effect between the H1 haplotype in the MAPT gene and SNPs in the SNCA gene on disease. Variation in each gene was associated with PD risk, indicating independent effects.
Alzheimer Disease
Conrad et al. (2002) identified a single-nucleotide polymorphism that results in a gly7-to-arg (G7R) change in the saitohin gene which appeared to be overrepresented in the homozygous state in late-onset Alzheimer disease subjects.
Because the MAPT R406W mutation (157140.0003) can cause a clinical picture closely resembling Alzheimer disease (see 104300) and quite different from frontotemporal dementia with parkinsonism, Rademakers et al. (2003) stated that MAPT should be considered a candidate gene for clinical Alzheimer disease families in which mutations in known Alzheimer disease genes have been excluded.
Myers et al. (2005) reported that the H1c subhaplotype of MAPT on the background of the well-described H1 clade was associated with risk of Alzheimer disease in 360 autopsy-confirmed cases with ages at death over 65 years of age and 252 controls.
Kwok et al. (2008) showed that the MAPT G-to-A allele of rs242557, which partially defines the H1c subhaplotype, results in increased MAPT gene expression. The authors also provided evidence that the H1/H2 MAPT haplotype interacts with functional SNPs in the GSK3B gene (605004) to affect risk of Alzheimer disease.
Among 22 patients with FTLD (600274) due to a MAPT mutation, Whitwell et al. (2009) found different patterns of gray matter atrophy using MRI voxel-based morphometry. All patients showed gray matter loss in the anterior temporal lobes, with varying degrees of involvement of the frontal and parietal lobes. Within the temporal lobe, individuals with the IVS10+16 (157140.0006), IVS10+3, N279K (157140.0009), or S305N (157140.0010) mutations showed gray matter loss particularly affecting the medial temporal lobes, including the hippocampus and amygdala. These mutations are all predicted to influence the alternative splicing of MAPT pre-mRNA, resulting in increased 4R tau isoforms. In contrast, patients with the P301L (157140.0001) or V337M (157140.0008) mutations showed gray matter loss particularly affecting the inferior and lateral temporal lobes, with a relative sparing of the medial temporal lobe. P301L and V337M mutation carriers also showed gray matter loss in the basal ganglia. These mutations are predicted to affect the structure and functional properties of the tau protein, which are more prone to aggregation. The different patterns suggested a potential difference in mutant protein function resulting from different pathogenic mutations.
Stambolic et al. (1996) observed that lithium treatment of intact eukaryotic cells inhibits GSK3-dependent phosphorylation of the microtubule-associated protein tau, a putative GSK3 substrate.
Using Western blot analysis, Hiesberger et al. (1999) demonstrated that mice lacking either Reelin (RELN; 600514) or Vldlr (192977) and ApoER2 (LRP8; 602600) exhibit a dramatic increase in the phosphorylation level of the microtubule-stabilizing protein tau.
To model tauopathies, Ishihara et al. (1999) overexpressed the smallest human tau isoform in the central nervous system of transgenic mice. These mice acquired age-dependent central nervous system pathology similar to FTDP17, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules, and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These transgenic mice recapitulated key features of tauopathies and provided models for elucidating mechanisms underlying diverse tauopathies, including Alzheimer disease.
To model aspects of tau-related physiology and pathology, Spittaels et al. (1999) generated transgenic mice that overexpressed the 4R human tau isoform specifically in neurons. The mice developed axonal degeneration in brain and spinal cord, characterized by reduced or blocked axonal transport and axonal dilations as well as sensorimotor deficits, in the absence of intraneuronal neurofibrillary tangles. Spittaels et al. (1999) noted that excess normal tau might be sufficient to cause neuronal injury and suggested that excess of the 4R tau protein interferes with kinesin-dependent transport by saturating binding sites on microtubules. Spittaels et al. (2000) showed that when GSK3-beta (GSK3B; 605004) is expressed in these transgenic mice there is a strong reduction in the number of axonal dilations and a nearly complete alleviation of motor impairments, presumably by phosphorylation of tau, which then reduces the binding of tau to microtubules. Although more phosphorylated tau was available, neither PHFs nor tangles were formed.
Tesseur et al. (2000) observed that overexpression of human APOE4 in neurons of transgenic mice resulted in hyperphosphorylation of tau, and Tesseur et al. (2000) demonstrated that these mice exhibited widespread astrogliosis in the brain, impaired axonal transport, and axonal degeneration.
Lewis et al. (2000) demonstrated that expression of human tau containing the most common mutation, P301L (157140.0001), results in motor and behavioral deficits in transgenic mice, with age- and gene-dose-dependent development of neurofibrillary tangles (NFT). This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. Abnormalities were seen not only in the central nervous system; a peripheral neuropathy and skeletal muscle involvement with neurogenic atrophy were also found.
Gotz et al. (2001) demonstrated that injection of beta-amyloid (104760) A-beta-42 fibrils into the brains of P301L mutant tau transgenic mice causes 5-fold increases in the numbers of neurofibrillary tangles in cell bodies within the amygdala from where neurons project to the injection sites. Gallyas silver impregnation identified neurofibrillary tangles that contained tau phosphorylated at serine-212/threonine-214 and serine-422. Neurofibrillary tangles were composed of twisted filaments and occurred in 6-month-old mice as early as 18 days after A-beta-42 injections. Gotz et al. (2001) concluded that their data support the hypothesis that A-beta-42 fibrils can accelerate neurofibrillary tangle formation in vivo.
Lewis et al. (2001) crossed JNPL3 transgenic mice expressing a mutant tau protein, which developed neurofibrillary tangles and progressive motor disturbance, with Tg2576 transgenic mice expressing mutant beta-amyloid precursor protein (APP), thus modulating the APP-A-beta environment. The resulting double-mutant (tau/APP) progeny and the Tg2576 parental strain developed amyloid-beta deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. Lewis et al. (2001) concluded that either APP or amyloid-beta influences the formation of neurofibrillary tangles. The interaction between amyloid-beta and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer disease.
Nguyen et al. (2001) found that hyperphosphorylation of neurofilament and tau proteins was associated with abnormal elevation of the p25/p35 (see 603460) ratio and Cdk5 (123831) activity in the spinal cord of a transgenic mouse model of amyotrophic lateral sclerosis (ALS; 105400).
Using proteomic analysis, David et al. (2005) showed that expression of human P301L mutant tau in transgenic mice resulted in distinct modifications of the brain proteome, suggesting alterations in the mitochondrial electron transport chain, cellular antioxidant capacities, and synaptic properties. Subsequent examination of complex V levels in brains of FTDP17 patients carrying the P301L tau mutation confirmed the observations made in P301L tau transgenic mice and suggested that P301L mutant tau pathology caused a specific mitochondrial dysfunction in humans and mice. In agreement, transgenic P301L tau mice exhibited an initial defect in mitochondrial function with reduced complex I activity, which, with age, translated into a mitochondrial respiration deficiency with diminished ATP synthesis corresponding to reduced complex V activity. P301L mutant tau also caused higher oxidative stress, modified lipid peroxidation levels, and upregulated antioxidant enzyme activities, without reducing mitochondrial numbers or significantly changing transport of mitochondria along neurites. In addition, P301L mutant tau decreased the membrane potential of cortical brain cells in transgenic mice, as these cells became more susceptible to A-beta treatment.
Taniguchi et al. (2005) found that transgenic mice expressing human N279K (157140.0009) mutant tau were viable, with normal feeding and body weight. However, transgenic mice displayed cognitive/sensorimotor deficits when evaluated by a comprehensive battery of tests.
SantaCruz et al. (2005) found that mice expressing a repressible human tau variant developed progressive age-related neurofibrillary tangles, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered and neuron numbers stabilized, but neurofibrillary tangles continued to accumulate. SantaCruz et al. (2005) concluded that neurofibrillary tangles are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.
Karsten et al. (2006) identified the Npepps gene (606793) as a tau modifier by using a cross-species functional genomic approach to analyze gene expression in mice. Npepps expression was increased in multiple brain regions in a mouse model of frontotemporal dementia (FTD) compared to control mice. In Drosophila, Npepps protected against tau-induced neurodegeneration, whereas loss of Npepps exacerbated neurodegeneration. Immunoblot, SDS-PAGE, and Western blot analyses showed that human NPEPPS directly proteolyzed and significantly diminished human tau. Western blot analysis of 6 brains derived from human FTD patients showed increased NPEPPS expression, particularly in the cerebellum.
Yoshiyama et al. (2007) developed transgenic mice expressing wildtype human MAPT or MAPT with the pro301-to-ser (P301S; 157140.0012) mutation. P301S mice developed synaptic pathology and microgliosis in hippocampus at 3 months of age, followed by synaptic dysfunction at 6 months of age, prior to neuron loss and formation of neurofibrillary tangles. Yoshiyama et al. (2007) concluded that synaptic pathology and microgliosis may be the earliest manifestation of tauopathies.
Chatterjee et al. (2009) employed a Drosophila model of tauopathy to investigate the interdependence of tau kinases in regulating the phosphorylation and toxicity of tau in vivo. Tau mutants resistant to phosphorylation by Par1, the fly homolog of MARK1 (606511), were less toxic than wildtype tau; however, this was not due to their resistance to phosphorylation by Shaggy (GSK3B; 605004). On the contrary, a tau mutant resistant to phosphorylation by Shaggy retained substantial toxicity and had increased affinity for microtubules compared with wildtype tau. Chatterjee et al. (2009) suggested that, in addition to tau phosphorylation, microtubule binding may play a crucial role in the regulation of tau toxicity when misexpressed.
Expression of human tau in C. elegans neurons causes accumulation of aggregated tau leading to neurodegeneration and uncoordinated movement. Guthrie et al. (2009) used this model of human tauopathy disorders to screen for genes required for tau neurotoxicity. Recessive loss-of-function mutations in the Sut2 locus (ZC3H14; 613279) suppress the worm Unc phenotype, tau aggregation, and neurodegenerative changes caused by human tau. Guthrie et al. (2009) cloned the Sut2 gene and found that it encodes a novel subtype of CCCH zinc finger protein conserved across animal phyla. Sut2 shares significant identity with the mammalian SUT2. A yeast 2-hybrid screen revealed that Sut2 bound to Zyg12, the sole C. elegans HOOK protein family member (see 607820). Likewise, Sut2 bound Zyg12 in in vitro protein binding assays. Loss of Zyg12 led to a marked upregulation of Sut2 protein supporting the connection between Sut2 and Zyg12. The human ortholog of Sut2 bound only to HOOK2 (607824), suggesting that the interaction between Sut2 and HOOK family proteins may be conserved across animal phyla.
Iijima-Ando et al. (2010) showed that the DNA damage-activated checkpoint kinase-2 (CHK2; 604373) is a novel tau kinase. Overexpression of Drosophila Chk2 increased tau phosphorylation at ser262 and enhanced tau-induced neurodegeneration in transgenic flies expressing human tau. The nonphosphorylatable ser262-to-ala mutation abolished Chk2-induced enhancement of tau toxicity, suggesting that the ser262 phosphorylation site may be involved in the enhancement of tau toxicity by Chk2. In vitro kinase assays revealed that human CHK2 and a closely related checkpoint kinase, CHK1 (603078), directly phosphorylated human tau at ser262. Drosophila Chk2 did not modulate the activity of the fly homolog of microtubule affinity regulating kinase (see MARK3, 602678), which has been shown to be a physiologic tau ser262 kinase. Iijima-Ando et al. (2010) suggested that CHK1 and CHK2 may be involved in tau phosphorylation and toxicity in the pathogenesis of Alzheimer disease.
Using transgenic Drosophila expressing human A-beta-42 (APP; 104760) and tau, Iijima et al. (2010) showed that tau phosphorylation at ser262 plays a critical role in A-beta-42-induced tau toxicity. Coexpression of A-beta-42 increased tau phosphorylation at AD-related sites including ser262, and enhanced tau-induced neurodegeneration. In contrast, formation of either sarkosyl-insoluble tau or paired helical filaments was not induced by A-beta-42. Coexpression of A-beta-42 and tau carrying the nonphosphorylatable ser262ala mutation did not cause neurodegeneration, suggesting that the ser262 phosphorylation site is required for the pathogenic interaction between A-beta-42 and tau. CHK2 phosphorylates tau at ser262 and enhances tau toxicity in a transgenic Drosophila model (Iijima-Ando et al., 2010). Exacerbation of A-beta-42-induced neuronal dysfunction by blocking tumor suppressor p53 (191170), a key transcription factor for the induction of DNA repair genes, in neurons suggested that induction of a DNA repair response is protective against A-beta-42 toxicity. The authors concluded that tau phosphorylation at ser262 is crucial for A-beta-42-induced tau toxicity in vivo, and they suggested a model of AD progression in which activation of DNA repair pathways is protective against A-beta-42 toxicity but may trigger tau phosphorylation and toxicity in AD pathogenesis.
Using Drosophila and mouse models of tauopathies, Falzone et al. (2010) showed that reductions in axonal transport by reduction in kinesin-1 (KLC1; 600025) expression can exacerbate human tau protein hyperphosphorylation, formation of insoluble aggregates, and tau-dependent neurodegeneration. The authors hypothesized that nonlethal reductions in axonal transport, and perhaps other types of minor axonal stress, are sufficient to induce and/or accelerate abnormal tau behavior characteristic of Alzheimer disease and other neurodegenerative tauopathies.
Xu et al. (2010) generated transgenic mice overexpressing full-length human TTBK1 and tau with the P301L mutation. Transgenic mice developed age-dependent pathology in central nervous system, including intraneuronal accumulation of phosphorylated tau, accumulation of sarkosyl-soluble phospho-tau multimers, Cdk5 and Gsk3-beta activation, locomotor dysfunction, and motor neuron degeneration. The results suggested that TTBK1 is involved in phosphorylation-dependent generation of pathogenic tau aggregation.
Lei et al. (2012) found decreased levels of soluble tau and increased iron levels in the substantia nigra of postmortem samples from patients with Parkinson disease compared to controls. The tau loss was independent of neuronal loss. Similar changes were observed in the MPTP mouse model of Parkinson disease. Mapt-knockout mice developed age-dependent brain atrophy, iron accumulation in various brain regions, and neuronal loss in the substantia nigra, as well as cognitive deficits and parkinsonism. These changes could be prevented by oral treatment with a moderate iron chelator, clioquinol. In primary neuronal cell cultures, Lei et al. (2012) found that loss of tau caused iron retention by decreasing the surface expression of APP, which interacts with ferroportin (SLC40A1; 604653) to accomplish neuronal iron efflux. The findings suggested that tau is needed to prevent age-related damage, that loss of soluble tau contributes to toxic neuronal iron accumulation in Alzheimer disease, Parkinson disease, and other tauopathies, and that pharmacologic intervention in this process may ameliorate the disease.
Taylor et al. (2018) showed that transgenic C. elegans expressing the kinase catalytic domain of human TTBK1 or TTBK2 (611695) were behaviorally normal. However, C. elegans coexpressing TTBK1 or TTBK2 with tau caused neurodegeneration, behavioral abnormalities, aberrant phosphorylation, and shortened lifespan. Coexpression of TTBK2 with high levels of tau resulted in lethality.
Przybyla et al. (2020) found that transgenic mice expressing human tau with a pro301-to-ser (P301S) mutation displayed progressive spatial learning deficits accompanied by reduced synaptic plasticity and aberrant neuronal network activity in brain. Mutant mice presented with an immediate early gene response, consistent with increased neuronal activity. Increased immediate early gene activity was confined to neurons harboring tau pathology, providing a cellular link between aberrant tau and network dysfunction.
Neve et al. (1986) noted that 1 of their tau clones hybridized to both chromosome 17 and to an additional region of homology on chromosome 6q21 (MAPTL). They suggested that either the 2 clones represented 2 different tau genes on different chromosomes, or that the 2 clones encoded different regions of the same expressed gene on chromosome 17 and only one of them bore homology to a nonexpressed pseudogene on chromosome 6.
Volz et al. (1994) reported that MAPTL clustered with FTHP1 and GSTA1 (138359) in the region 6p21.1-p12, with the map order unknown.
In a large Dutch kindred with frontotemporal dementia (600274) reported by Heutink et al. (1997), Hutton et al. (1998) found a pro301-to-leu mutation (P301L) in exon 10 of the MAPT gene. The same mutation was found in a small kindred from the United States. This substitution occurred in a highly conserved region of the MAPT sequence, where a proline residue was found in all mammalian species from which tau had been cloned to that time. The P301L mutation would affect only the 4-repeat tau isoforms because exon 10 is spliced out of mRNA that encodes the 3-repeat isoforms. Analysis of tau aggregates in affected brains from the U.S. kindred revealed that these consist mainly of 4-repeat isoforms, consistent with the mutation affecting exon 10.
In a note added in proof, Poorkaj et al. (1998) described finding a C-to-T transition at nucleotide 728 of the MAPT gene in a newly ascertained family with FTDP17. The mutation resulted in a PRO243LEU mutation. This is the same mutation as that reported by Hutton et al. (1998), who used a different numbering system for the nucleotides and codons. At the time the paper of Poorkaj et al. (1998) was submitted, the longest amino acid form of tau in the database did not include all of the alternatively spliced exons (Poorkaj, 1998).
MAPT transcripts that contain this exon 10 mutation encode tau isoforms with 4 microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with 3 MT-binding repeats (3Rtau). Clark et al. (1998) found that brains of patients with the P301L missense mutation contained aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration.
Using purified recombinant proteins, Alonso et al. (2004) showed that several FTDP17-associated tau mutations, including P301L, made tau a more favorable substrate for abnormal hyperphosphorylation compared with wildtype tau. Both the phosphorylation kinetics, due to induced conformational changes, and the phosphorylation stoichiometry, due to increased phosphorylation of more than a single site, were more favorable in the mutant proteins. The mutant proteins polymerized into filaments more readily than wildtype tau, leading to decreased ability to bind wildtype tau.
Using proteomic analysis, David et al. (2005) showed that expression of human P301L mutant tau in transgenic mice resulted in distinct modifications of the brain proteome, suggesting alterations in the mitochondrial electron transport chain, cellular antioxidant capacities, and synaptic properties. Subsequent examination of complex V levels in brains of FTDP17 patients carrying the P301L tau mutation confirmed the observations made in P301L tau transgenic mice and suggested that P301L mutant tau pathology caused a specific mitochondrial dysfunction in humans and mice. In agreement, transgenic P301L tau mice exhibited an initial defect in mitochondrial function with reduced complex I activity, which, with age, translated into a mitochondrial respiration deficiency with diminished ATP synthesis corresponding to reduced complex V activity. P301L mutant tau also caused higher oxidative stress, modified lipid peroxidation levels, and upregulated antioxidant enzyme activities, without reducing mitochondrial numbers or significantly changing transport of mitochondria along neurites. In addition, P301L mutant tau decreased the membrane potential of cortical brain cells in transgenic mice, as these cells became more susceptible to A-beta treatment.
Using purified recombinant proteins, Aoyagi et al. (2007) showed that P301L mutant tau assembled into nuclei more rapidly than wildtype tau or R406W (157140.0003) mutant tau. However, P301L mutant nuclei could only promote assembly of P301L mutant tau into filaments, whereas wildtype and R406W mutant nuclei had the ability to seed both wildtype and P301L mutant tau. Pronase digestion experiments revealed conformational differences between P301L mutant tau and wildtype or R406W mutant tau. The core structure of P301L mutant tau seeds was distinct from that of wildtype tau seeds, regardless of phosphorylation state, whereas R406W mutant tau seeds had a core structure similar to that of wildtype tau seeds.
Donker Kaat et al. (2009) identified a P301L mutation in 1 of 172 probands with progressive supranuclear palsy (601104).
In a second large Dutch kindred with frontotemporal dementia (600274) reported by Heutink et al. (1997) as an example of hereditary Pick disease, Hutton et al. (1998) found a gly272-to-val mutation (G272V) that affected a highly conserved residue within the microtubule-associated domain, encoded by exon 9 of the MAPT gene.
Using purified recombinant proteins, Alonso et al. (2004) showed that several FTDP17-associated tau mutations, including G272V, made tau a more favorable substrate for abnormal hyperphosphorylation compared with wildtype tau. Both the phosphorylation kinetics, due to induced conformational changes, and the phosphorylation stoichiometry, due to increased phosphorylation of more than a single site, were more favorable in the mutant proteins. The mutant proteins polymerized into filaments more readily than wildtype tau, leading to decreased ability to bind wildtype tau.
In affected members of a family from the United States with autosomal dominant frontotemporal dementia (600274) originally reported by Reed et al. (1997), Hutton et al. (1998) identified a heterozygous arg406-to-trp mutation (R406W) in the MAPT gene. Neuropathologic examination identified tau-positive intraneuronal neurofibrillary tangles similar to those found in Alzheimer disease (see 104300).
Connell et al. (2001) studied the in vitro phosphorylation of several tau mutants by glycogen synthase kinase 3-beta and confirmed previous findings that the R406W mutation had the surprising effect of reducing tau phosphorylation in cells, compared to both the wildtype and other mutant forms. Connell et al. (2001) suggested that reduced tau phosphorylation and a minor loss of function associated with R406W may contribute to the later onset and somewhat milder phenotype found in families with this mutation.
Tatebayashi et al. (2002) showed that the expression of the R406W mutation in transgenic mice resulted in the development of congophilic hyperphosphorylated tau inclusions in forebrain neurons. These inclusions appeared as early as 18 months of age. As with human cases, tau inclusions were composed of both mutant and endogenous wildtype tau, and were associated with microtubule disruption and flame-shaped transformations of the affected neurons. Behaviorally, aged transgenic mice had associative memory impairment without obvious sensorimotor deficits. Therefore, these mice exhibited a phenotype mimicking R406W FTDP17 (frontotemporal dementia and parkinsonism linked to chromosome 17).
Saito et al. (2002) reported a patient who presented at age 47 years with psychiatric disturbances, primarily delusions, who developed overt dementia by age 52, and died at age 53. There was rapid progression in the last year of life. His father had had a similar illness. Postmortem examination revealed neuronal loss associated with neurofibrillary tangles and neuropil threads, accentuated in the medial temporal lobe, that were immunoreactive for the tau protein. Molecular analysis revealed an R406W mutation.
Rademakers et al. (2003) suggested that the R406W mutation can cause a clinical picture closely resembling Alzheimer disease and quite different from frontotemporal dementia with parkinsonism. They described a 6-generation Belgian family that carried the R406W mutation and had such clinical features, and pointed to reports of 2 other families that carried the R406W mutation and had similar clinical characteristics: 1 from the U.S. Midwest with a Danish ancestor (Reed et al., 1997) and 1 from the Netherlands (van Swieten et al., 1999). Haplotype data ruled against a founder effect for the origin of the mutation in western Europe. Rademakers et al. (2003) stated that their report illustrated the phenotypic heterogeneity of MAPT mutations and reemphasized that MAPT should be considered a candidate gene for clinical Alzheimer disease families in which mutations in known Alzheimer disease genes have been excluded.
Using purified recombinant proteins, Alonso et al. (2004) showed that several FTDP17-associated tau mutations, including R406W, made tau a more favorable substrate for abnormal hyperphosphorylation compared with wildtype tau. Both the phosphorylation kinetics, due to induced conformational changes, and the phosphorylation stoichiometry, due to increased phosphorylation of more than a single site, were more favorable in the mutant proteins. The mutant proteins polymerized into filaments more readily than wildtype tau, leading to decreased ability to bind wildtype tau.
Using purified recombinant proteins, Aoyagi et al. (2007) showed that P301L (157140.0001) mutant tau assembled into nuclei more rapidly than wildtype tau or R406W mutant tau. However, P301L mutant nuclei could only promote assembly of P301L mutant tau into filaments, whereas wildtype and R406W mutant nuclei had the ability to seed both wildtype and P301L mutant tau. Pronase digestion experiments revealed conformational differences between P301L mutant tau and wildtype or R406W mutant tau. The core structure of P301L mutant tau seeds was distinct from that of wildtype tau seeds, regardless of phosphorylation state, whereas R406W mutant tau seeds had a core structure similar to that of wildtype tau seeds.
In addition to 3 missense mutations, Hutton et al. (1998) found 3 heterozygous mutations in a cluster of 4 nucleotides 13- to 16-bp 3-prime of the exon 10 5-prime splice site of the MAPT gene in families with frontotemporal dementia with parkinsonism (600274). Six families had mutations at 1 of these 3 sites, including 4 families in which the disorder had previously been linked to chromosome 17. One of these linked families was reported by Wilhelmsen et al. (1994) as disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC; 600274). In this family, the mRNA showed a C-to-U transition in the stem-loop structure at position 14 in the splice donor site of intron 10.
One of the splice site mutations identified by Hutton et al. (1998) in families with frontotemporal dementia with parkinsonism (600274) was an A-to-G transition at position 13 in intron 10.
In a British patient with frontotemporal dementia, Pickering-Brown et al. (2002) identified the tau IVS10 +13 mutation. He presented with apathy and inertia, and later developed semantic loss.
In an Australian family with frontotemporal dementia with parkinsonism (600274), Hutton et al. (1998) found a C-to-T change in the MAPT mRNA at position 16 of the splice donor site of intron 10. The mutation resulted in an increased incorporation of exon 10 in MAPT mRNA levels, which increased the proportion of tau isoforms containing 4 microtubule-binding domains.
Goedert et al. (1999) identified a heterozygous IVS10+16C-T mutation in the MAPT gene in affected members of a family with frontotemporal dementia and extrapyramidal signs. Initial neuropathologic examination (Lanska et al., 1994) showed prominent subcortical gliosis (221820), but later studies by Goedert et al. (1999) showed hyperphosphorylated tau in both neurons and glial cells with wide twisted ribbons made of 4-repeat tau isoforms. The molecular findings confirmed the diagnosis. Goedert et al. (1999) noted that phenotypic heterogeneity associated with MAPT mutations has led to classification of related diseases into distinct entities.
Janssen et al. (2002) described the clinical characteristics of 9 families with frontotemporal dementia and the tau exon 10 +16 mutation and found considerable variation in age at onset and duration of disease both between and within families, suggesting the influence of other genetic or environmental factors.
Pickering-Brown et al. (2002) reported 8 British families with frontotemporal dementia from North Wales in which affected members had the tau exon 10 +16 mutation. Clinical features included disinhibition, restless overactivity, fatuous affect, puerile behavior, verbal and motor stereotypes, and semantic loss. In 5 of these 8 families, Pickering-Brown et al. (2004) found a common 3-cM haplotype flanked by markers D17S1860 and D17S806. An affected Australian pedigree (Dark, 1997), 7 patients from London (Janssen et al., 2002; Lantos et al., 2002), and 2 patients from Philadelphia (Poorkaj et al., 2001) had the same haplotype. The disease haplotype was not observed in 100 geographically matched control chromosomes. Pickering-Brown et al. (2004) concluded that the exon 10 +16 mutation represents a founder effect that originated in North Wales. They demonstrated that the mutation is on the H1 tau haplotype.
Doran et al. (2007) reported a large family from Liverpool, England, in which 8 individuals had frontotemporal dementia associated with the IVS10+16C-T mutation. All patients were initially diagnosed with Alzheimer disease (104300) because of presentation of memory deficits and word-finding difficulties. Prototypic features of frontotemporal dementia, such as disinhibition and personality changes, were not noted initially. Doran et al. (2007) noted the phenotypic variability of this mutation.
Colombo et al. (2009) noted that the identification of the IVS10+16C-T mutation in patients from North America and the U.K. support the hypothesis of a founder effect of British origin. Using several different methods of haplotype analysis, the authors estimated that the mutation occurred about 23 generations ago, around 1300 A.D., before Welsh people started emigrating to the U.S. and Australia, where they introduced the mutation.
In a kindred known to have presenile dementia identified as multiple system tauopathy with presenile dementia (MSTD; 600274) in individuals in 5 successive generations, Spillantini et al. (1998) found a G-to-A transition in the nucleotide 3-prime of the exon 10 splice donor site. It was identified in 11 affected family members and segregated with the disease haplotype in other family members. Examination of the nucleotide sequence of exon 10 and the 5-prime intron junction identified a predicted stem-loop structure that encompassed the last 6 nucleotides at the 3-prime end of exon 10 and 19 nucleotides of the intron, including the GT splice donor site. The G-to-A transition destabilized this stem-loop structure. The disorder was associated with an abnormal preponderance of soluble tau protein isoforms with 4 microtubule-binding repeats over isoforms with 3 repeats. This was thought most likely to account for the previous finding that sarkosyl-insoluble tau protein extracted from the filamentous deposits in familial MSTD consists only of tau isoforms with 4 repeats. The departure from the normal ratio of 4-repeat to 3-repeat tau isoforms leads to the formation of abnormal tau filaments. The dysregulation of tau protein production in turn leads to neurodegeneration.
Poorkaj et al. (1998) identified 9 DNA sequence variants in 2 families with what they referred to as FTDP17 (600274); 8 of these were also identified in controls and were thus considered polymorphisms. The ninth variant, VAL279MET, was found in 1 FTDP17 family, but not in the other. (This mutation is designated val337 to met in the numbering used by Hutton et al. (1998); see 157140.0001.) The change was considered positive since it occurred in a highly conserved residue and a normal valine is found at this position in all 3 tau interrepeat sequences and in other MAPT homologs. Furthermore, the mutation cosegregated with the disease in the family and was not found in normal controls. At the time that the paper of Poorkaj et al. (1998) was submitted, the longest amino acid form of tau in the database did not include all of the alternatively spliced exons (Poorkaj, 1998).
Using purified recombinant proteins, Alonso et al. (2004) showed that several FTDP17-associated tau mutations, including V337M, made tau a more favorable substrate for abnormal hyperphosphorylation compared with wildtype tau. Both the phosphorylation kinetics, due to induced conformational changes, and the phosphorylation stoichiometry, due to increased phosphorylation of more than a single site, were more favorable in the mutant proteins. The mutant proteins polymerized into filaments more readily than wildtype tau, leading to decreased ability to bind wildtype tau.
Sohn et al. (2019) found that the FTD-associated tau V337M mutant shortened the axon initial segment (AIS) and impaired AIS plasticity in human induced pluripotent stem cell (iPSC)-derived neurons. Electrophysiologic properties of tau V337M neurons revealed that the mutation also impaired homeostatic control of spontaneous neuronal activity in response to depolarization. End-binding protein-3 (EB3, or MAPRE3; 605788), a component of the AIS cytoskeleton, was associated with ANKG (106280) and tau in the AIS submembrane region of human neurons. However, the V337M mutation increased the binding affinity of tau with EB3, leading to increased EB3 accumulation in the AIS in tau V337M mutant neurons. EB3 accumulation increased its interaction with ANKG and promoted its structural stability via physical interaction with microtubules, thereby impairing AIS plasticity in tau V337M mutant neurons.
In affected members of a kindred with pallidopontonigral degeneration (PPND; 600274) originally reported by Wszolek et al. (1992), Clark et al. (1998) identified an asn279-to-lys (N279K) mutation in exon 10 of the MAPT gene. Although the clinical features and associated regional variations in the neuronal loss observed in different kindreds with frontotemporal dementia and parkinsonism linked to chromosome 17 are diverse, the diagnostic lesions in the brain are tau-rich filaments in the cytoplasm of specific subpopulations of neurons and glial cells. The insoluble tau aggregates isolated from brains of patients with the N279K mutation were analyzed by immunoblotting using tau-specific antibodies. For each of 3 mutations, abnormal tau with an apparent relative mass of 64 and 69 kD was observed. The dephosphorylated material comigrated with tau isoforms containing exon 10 having 4 microtubule-binding repeats but not with 3-repeat tau. Thus, the brains contained aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration.
Delisle et al. (1999) reported 2 French brothers with the N279K mutation who presented early in the fourth decade with a neurodegenerative disorder characterized by an akinetic rigid syndrome and dementia. There was widespread neuronal and glial tau accumulation in the cortex, basal ganglia, brainstem nuclei, and white matter.
Arima et al. (2000) reported 2 Japanese brothers with the N279K mutation who presented with frontotemporal dementia characterized by personality changes, behavioral disinhibition, asocial misconduct, recent memory deficits, and parkinsonism. The disease progressed in both patients, rendering them mute and bedridden with death at ages 57 and 50. Pathologic examination showed severe temporal lobe atrophy, neuronal loss, and tau-immunoreactive neurofibrillary tangles and cytoplasmic inclusions. There was also phosphorylated tau deposition in neurons of the spinal cord and degeneration of the lateral corticospinal tracts. Insoluble tau, mainly 4-repeat isoforms, with molecular masses of 64 and 69 kD were observed. The tau aggregates were found to be composed of paired hollow tubules, 11 to 12 nm in diameter. One of the patients had responded temporarily to L-DOPA therapy.
Yasuda et al. (1999) reported a Japanese patient with the N279K mutation who presented at 41 years of age with rapidly progressive parkinsonism which later included dementia, hallucinations, vertical gaze palsy, extensor plantar responses, frontal release signs, and incontinence. His sister had parkinsonism and dementia and died in her forties. Neuropathologic examination of the proband showed severe cortical atrophy, discoloration of the striatum, globus pallidus, and luysian body, and prominent depigmentation of the substantia nigra and locus ceruleus. In both cortical and subcortical regions, there was moderate to severe neuronal loss, astrocytic gliosis, tau-positive neuronal inclusion bodies, and loss of motor neurons. The authors termed this disease pallido-nigro-luysian degeneration. Wszolek et al. (2000) suggested that the disorder in the patient reported by Yasuda et al. (1999), in which parkinsonism was the initial prominent feature, is a subtype of FTDP17.
Tsuboi et al. (2002) analyzed clinical and genealogic records of 4 previously reported families with the N279K mutation: an American family (Clark et al., 1998), a French family (Delisle et al., 1999), and 2 Japanese families (Yasuda et al., 1999; Arima et al., 2000). The clinical phenotype was similar in all families: onset in the forties, survival time of 6 to 8 years, parkinsonism as the presenting sign, short or no response to L-DOPA treatment, progressive dementia, pyramidal dysfunction, and gaze palsy. Molecular genetic studies showed a shared disease haplotype between the 2 Japanese families, suggesting a founder effect. Tsuboi et al. (2002) suggested that FTDP17 could be divided into 2 major clinical groups, parkinsonism-predominant and dementia-predominant, and that patients with the N279K mutation fall into the former category. Tsuboi et al. (2002) also reported a previously undescribed Japanese patient with the N279K mutation and a similar phenotype.
Rademakers et al. (2004) likewise commented on the highly similar clinical phenotypes associated with the N279K mutation despite the occurrence on different genetic backgrounds. In the various families, the mean age at onset ranged from 41 to 47 years. In patients, typical parkinsonian features such as bradykinesia, rigidity, and postural instability were uniformly seen. Personality and behavioral changes and dementia also occurred during the course of the illness, but were less prominent.
Taniguchi et al. (2005) found that transgenic mice expressing human N279K mutant tau were viable, with normal feeding and body weight. However, transgenic mice displayed cognitive/sensorimotor deficits when evaluated by a comprehensive battery of tests.
Iijima et al. (1999) reported a Japanese family with early-onset hereditary frontotemporal dementia (600274) and a novel ser305-to-asn mutation in the tau gene. The patients presented with personality changes followed by impaired cognition and memory as well as disorientation, but minimal parkinsonism.
Murrell et al. (1999) described a gly389-to-arg (G389R) missense mutation in exon 13 of the MAPT gene in a patient with a condition closely resembling Pick disease (172700). When 38 years old, the proband presented with progressive aphasia and memory disturbance, followed by apathy, indifference, and hyperphagia. MRI showed the dramatic progression of cerebral atrophy. PET revealed marked glucose hypometabolism that was most severe in the left frontal, temporal, and parietal cortical regions. Rigidity, pyramidal signs, and profound dementia progressed until death at 43 years of age. A paternal uncle, who had died at 43 years of age, had presented with similar symptoms. The proband's brain showed numerous tau-immunoreactive Pick body-like inclusions.
Of 30 cases of pathologically confirmed Pick disease, Pickering-Brown et al. (2000) identified 2 mutations in the tau gene in 2 unrelated patients: a G-to-A change, resulting in a G389R substitution, and an A-to-C change, resulting in a lys257-to-thr substitution (157140.0014). The patient with the G389R mutation showed a decline in intellectual ability with forgetfulness, aggression, and a decline in personal hygiene at age 32, which progressed to death by age 37. Pathologic examination showed severe atrophy and neuronal loss in the frontal cortex with many tau-immunoreactive neuronal inclusions. In vitro, the G389R mutation reduced the ability of tau to promote microtubule assembly by 25 to 30%.
In affected members of a family with early-onset frontotemporal dementia with parkinsonism (600274) and seizures, Sperfeld et al. (1999) identified a 1137C-T transition in exon 10 of the MAPT gene, resulting in a pro301-to-ser (P301S) substitution.
In a father and son with frontotemporal dementia and corticobasal degeneration, respectively, Bugiani et al. (1999) identified a P301S substitution in the MAPT gene. Both individuals developed rapidly progressive disease in the third decade. Neuropathic examination of the father showed extensive filamentous pathology made of hyperphosphorylated tau protein. Recombinant P301S tau protein showed a greatly reduced ability to promote microtubule assembly.
Yasuda et al. (2000) identified a P301S mutation in the MAPT gene in a Japanese man with onset of parkinsonism at age 37 and rapidly progressive frontotemporal dementia beginning at age 39. Citing earlier reports of mutations at the same position, the authors noted that codon 301 of the tau gene is a hotspot of pathogenic mutations and that the mutations exhibit variable phenotypes (see P301L; 157140.0001).
Lossos et al. (2003) identified the P301S mutation in 3 affected members of a Jewish family of Algerian origin with rapidly progressive frontotemporal dementia with parkinsonism. Disease onset was characterized by personality changes in the late thirties, followed by progressive cognitive and motor deterioration leading to akinetic mutism or death within 3 to 5 years. Werber et al. (2003) identified the P301S mutation in a 39-year-old Jewish woman of Algerian origin with frontotemporal dementia with parkinsonism. Family history revealed 4 affected first-degree relatives, 1 of whom was still alive and also carried the mutation. The families reported by Lossos et al. (2003) and Werber et al. (2003) were members of an extended Israeli-French kindred (Yasuda et al., 2005).
Yasuda et al. (2005) reported another Japanese family in which 6 members had frontotemporal dementia and parkinsonism caused by a heterozygous P301S mutation. Age at disease onset ranged from 28 to 40 years, and clinical findings were characterized by parkinsonism in all patients with dementia reported only in the 3 younger patients who had detailed medical histories. Neuropsychiatric features of these 3 patients included emotional incontinence, euphoria, apathy, and perseveration. One patient had psychotic features. Neuropathologic examination of these 3 patients showed neuronal loss and gliosis most prominent in the substantia nigra, globus pallidus, and subthalamic nucleus associated with neuropil thread-rich, tau-containing lesions. Yasuda et al. (2005) noted the phenotypic variability associated with the P301S mutation.
In a family with frontotemporal dementia (600274), previously reported by Brown et al. (1996) as having corticobasal degeneration, Spillantini et al. (2000) identified a silent mutation in exon 10 of the tau gene, resulting in exon trapping, or the inclusion of multiple copies of exon 10 in the mRNA transcript. This mutation was thought to lead to an abnormal preponderance of soluble tau protein isoforms with 4 microtubule-binding repeats over isoforms with 3 repeats, perhaps by disrupting a cis-acting element in the region of exon 10. Affected members demonstrated progressive dementia beginning in the fifth or sixth decade with extensive tau pathology and frontotemporal atrophy.
In a patient with familial frontotemporal dementia (600274), Lippa et al. (2000) identified a 1025A-T transversion in exon 12 of the tau gene, resulting in a glu342-to-val (E342V) substitution. The authors found that the levels of the 4R0N isoform were increased in all brain regions, whereas the 4RN1 and 4RN2 isoforms were decreased, a previously undescribed pathologic tau profile. Lippa et al. (2000) suggested that exon 12 may influence alternative splicing of other exons within the tau gene. Pathologic examination revealed frontotemporal neuron loss, intracytoplasmic tau aggregates, and paired helical tau filaments.
Of 30 cases of pathologically confirmed Pick disease (172700), Pickering-Brown et al. (2000) identified 2 mutations in the tau gene in 2 unrelated patients: an A-to-C change, resulting in a lys257-to-thr substitution, and the previously identified G389R substitution(157140.0011). Tau-immunoreactive Pick bodies and Pick cells were present. In vitro, the K257T mutation reduced the ability of tau to promote microtubule assembly by 70%.
In a patient with Pick disease (172700) characterized clinically by onset at age 52 of rapidly progressing decline of cognitive and behavioral abilities, and pathologically by severe temporal atrophy and the presence of Pick inclusion bodies and Pick cells, Neumann et al. (2001) identified a mutation in the tau gene, resulting in a lys369-to-ile (K339I) substitution in exon 12. The K369I mutation led to a 90% reduction in the rate of microtubule assembly, and the authors suggested that free mutant tau may assemble abnormally, leading to pathologic changes.
In a patient with late-onset (age 75 years) frontotemporal dementia with parkinsonism (600274), Hayashi et al. (2002) identified a G-to-A transition in exon 1 of the MAPT gene, resulting in an arg5-to-his (R5H) substitution. Pathologic examination revealed frontotemporal atrophy, neuronal loss, widespread tau-immunoreactive glial cytoplasmic inclusions, and insoluble tau filaments composed of 4-repeat tau. The mutation reduced the ability of tau to promote microtubule assembly and promoted fibril formation in vitro. The patient had an elderly brother with dementia who died at age 86 years.
In a patient who presented with presenile dementia characterized by mild memory problems at age 38 years, which progressed to major memory problems, personality changes, and aphasia at age 47, followed by death at age 53, Rosso et al. (2002) identified a C-to-T transition in exon 11 of the MAPT gene, resulting in a ser320-to-phe (S320F) substitution. Postmortem examination revealed findings consistent with Pick disease (172700), including focal bilateral atrophy of the anterior temporal lobes, extensive tau pathology in the form of Pick-like bodies, and insoluble tau-immunoreactive filaments. In vitro studies showed that the mutation resulted in a markedly reduced ability of tau to promote microtubule assembly.
Among 96 patients with progressive supranuclear palsy (601104), Poorkaj et al. (2002) identified 1 patient with a G-to-T mutation in a highly conserved position in exon 1 of the tau gene, resulting in an arg5-to-leu (R5L) substitution. Functional studies showed that the mutation delayed assembly initiation and lowered the mass of microtubules formed, but the assembly rate was increased compared to normal tau. The authors hypothesized a gain-of-function mutation. (Replacement of arginine by histidine at the same position (157170.0017) causes frontotemporal dementia with parkinsonism.)
In a Japanese patient with onset of FTDP17 (600274) at age 48 years and mental retardation since his first decade, Miyamoto et al. (2001) identified a heterozygous IVS10+11T-C change in the MAPT gene. An older brother, 1 sister, his mother, and grandfather had similar features, including mental retardation, but all had died and thus could not be tested. It was not clear if the mental retardation was related.
In a Spanish patient with atypical progressive supranuclear palsy (260540), born from a third-degree consanguineous marriage, Pastor et al. (2001) identified a homozygous 3-bp deletion (AAT) of asparagine at codon 296 in the MAPT gene. The proband and his brother demonstrated a remarkably similar phenotype characterized by onset in the late thirties of mild cognitive decline, inappropriate behavior, ocular movement abnormalities, and asymmetric parkinsonism. The parents were both heterozygous for the mutation, consistent with autosomal recessive inheritance. Two uncles, who were heterozygous for the mutation, developed late-onset typical Parkinson disease (168600). However, there were several asymptomatic heterozygous individuals over the age of 60 in the family, which the authors attributed to reduced penetrance. Pastor et al. (2001) noted that codon 296 lies in the region of the gene which alters splicing of exon 10 (see N296N; 157140.0013).
In a family with a variable neurodegenerative phenotype, including a progressive supranuclear palsy-like syndrome and parkinsonism, Rossi et al. (2004) identified a heterozygous deletion of the last 2 bases of codon 296 and the first base of codon 297, resulting in the deletion of asn296. The proband developed antecollis, dysarthria, postural instability with falls, slowing of ocular movements, and increased deep tendon reflexes at age 36 years, consistent with atypical PSNP. The mutation was also identified in a paternal aunt with typical dopa-responsive Parkinson disease, in 2 asymptomatic sisters of the proband, and in 3 asymptomatic daughters of a deceased paternal uncle who had atypical dopa-unresponsive Parkinson disease with pyramidal signs and cognitive impairment. The authors suggested incomplete penetrance of the disorder.
Oliva and Pastor (2004) noted that although the nucleotide changes reported by Rossi et al. (2004) were unique, the resultant amino acid change, deletion of asn296, is the same as that reported by Pastor et al. (2001); therefore the mutation should be considered the same. Following international recommendations (den Dunnen and Antonarakis, 2000), Oliva and Pastor (2004) proposed that the complete nomenclature for this mutation be designated 'c713-715delATA' at the cDNA level and 'delN296' at the protein level. Oliva and Pastor (2004) noted that functional studies had shown that the delN296 change can decrease the ability of 4-repeat tau to promote microtubule assembly (Yoshida et al., 2002). The authors suggested that heterozygosity for the delN296 mutation may be a risk factor for both a PSNP-like syndrome and Parkinson disease.
In 2 brothers with frontotemporal dementia (600274) characterized by onset of personality changes in the thirties with progression to dementia, Kobayashi et al. (2003) identified a heterozygous C-to-G transversion in exon 9 of the MAPT gene, resulting in a leu266-to-val (L266V) substitution. Their mother reportedly had a similar disease, but was not examined. The mutation was not present in 200 control subjects. In addition, both brothers were homozygotes for the H1 tau haplotype, which has been shown to be overrepresented in patients with FTD compared to controls. Brain neuropathologic examination in one brother showed frontotemporal atrophy with severe neuronal loss and gliosis in both the cortices and the substantia nigra. There were also tau-positive neuronal inclusions and tau-positive astrocytes with stout filaments. Recombinant tau proteins with the L266V mutation were less able to promote microtubule assembly than wildtype tau.
In 2 sibs from a consanguineous marriage who presented with a form of progressive supranuclear palsy (601104) characterized by fatal respiratory hypoventilation, Nicholl et al. (2003) identified a homozygous 1291C-T transition in exon 12 of the MAPT gene, resulting in a nonconserved ser352-to-leu (S352L) substitution in the N-terminal repeat of the tau protein. The authors called the disorder 'tauopathy and respiratory failure.' The 29-year-old pregnant sister developed dyspnea with stridor, and later had a generalized seizure that left her unconscious. Despite therapy, she died after 9 days. Her 30-year-old brother developed cough syncope, dyspnea, and central apnea, which progressed over 40 months, leading to death at age 34 years. During the illness, he showed slow smooth pursuit and impaired saccades, mild rigidity and bradykinesia, and myoclonic jerks. Neuropathologic examination showed widespread neuronal eosinophilia and pyknosis with gliosis in multiple brain regions, consistent with hypoxic brain damage. There was pervasive tau pathology in neuronal perikarya, neurites, and threads in the gray matter of the hippocampus, thalamus, and pons, but not in the cerebral cortex. Functional studies indicated that the mutated protein showed reduced binding to microtubules as well as increased fibrillization and aggregation. Both sibs carried the H1/H1 haplotype associated with PSP, Nicholl et al. (2003) commented on the unusual apparent autosomal recessive inheritance of this tauopathy. In a review of the role of tau in neurodegenerative diseases, Quadros et al. (2007) classified the disorder in the sibs reported by Nicholl et al. (2003) as PSP.
In affected members of 2 families from the Basque country in Spain with a tauopathy best described as frontotemporal dementia with parkinsonism (600274), Zarranz et al. (2005) identified a heterozygous A-to-T transversion in exon 11 of the MAPT gene, resulting in a lys317-to-met (K317M) substitution. Mean age at disease onset was 48 years, characterized by dysarthria and features of parkinsonism. All patients developed parkinsonism and a pyramidal syndrome, and half had amyotrophy. Other variable features included supranuclear gaze palsy, bulbar palsy, and dystonia. Although behavioral changes were not a prominent feature, most patients had frontal signs, and cognitive decline appeared late in the disease. All patients eventually became fully dependent, wheelchair- or bed-bound, tetraplegic, mute, and unable to feed orally. Neuropathologic examination showed frontal and temporal lobe atrophy, severe neuronal loss in the substantia nigra, and diffuse patchy neuronal loss and gliosis with numerous tau- and ubiquitin-positive neurons. Six of 7 spinal cords examined showed severe neuronal loss in the anterior horn and degeneration of the corticospinal tracts, similar to that seen in amyotrophic lateral sclerosis. Two bands of phospho-tau of 68 and 64 kD were observed in brain tissue from 1 patient. Zarranz et al. (2005) emphasized the motor component of the syndrome in these patients. Haplotype analysis suggested a common origin in the 2 families, and genealogic analysis identified a probable common ancestor born in 1782.
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