Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PP3, PP1, BS1
Clinical Phenotype Studied: rtvFTD, Alzheimer's Disease, Corticobasal Degeneration, FTD-Parkinsonism, bvFTD
Position: (GRCh38/hg38):Chr17:46024061 C>T
Position: (GRCh37/hg19):Chr17:44101427 C>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750424
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to TGG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 13
Research Models: 5

Findings

Summary
The R406W missense mutation in MAPT has been reported in multiple families worldwide, including families from Japan, the Netherlands, Sweden, Denmark, Belgium, Iran, the United Kingdom, China, and the United States. It is considered pathogenic for frontotemporal dementia (FTD), although the clinical presentation of mutation carriers is variable and often looks like Alzheimer’s disease (AD), especially in the early stages (e.g., see Ygland et al., 2018; Villa et al., 2024). Mutation carriers have been described as having clinical AD with late-onset frontal signs (Rademakers et al., 2003; Lindquist et al., 2008; Lindquist et al., 2009; Ikeuchi et al., 2008), as well as with FTD, most commonly the behavioral variant (bvFTD), with or without parkinsonism (Reed et al., 1997; Hutton et al., 1998; Rosso et al., 2003; Passant et al., 2004; Ostojic et al., 2004; van Swieten et al., 1999; Hirschbichler et al., 2015).

Additional diagnoses include right temporal variant FTD (rtvFTD) (Ulugut et al., 2021), corticobasal degeneration (Forrest et al., 2018), and unspecified, rapidly progressing dementia with psychosis (Saito et al., 2002). Even within the same family, clinical heterogeneity is apparent (e.g., Carney et al., 2013; Tolboom et al., 2010). In general, the R406W mutation is associated with a later age of onset and longer disease duration than other MAPT mutations (Ygland et al., 2018), although early onset and rapid progression also occur (e.g., Saito et al., 2002).

In an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature, nine families, including 67 carriers, were reported. Thirty-one of these carriers were diagnosed with behavioral variant FTD (bvFTD), 33 with dementia not otherwise specified, and three with AD (Moore et al., 2020, suppl tables 5-6).  However, another study that reviewed data from seven new carriers and 66 previously reported carriers found that the most common clinical diagnosis was AD (Ygland et al., 2018). In this study, memory loss was the most frequent symptom, behavioral alterations and language impairment were less common, and parkinsonism was rare. Median age at onset was 56 years and median disease duration 13 years.

Patterns of autosomal dominant inheritance across three or more generations have been observed in multiple families and segregation of the mutation with disease has been described (e.g., Hutton et al., 1998; Ygland et al., 2018; Rademakers et al., 2003; Gossye et al., 2023; Lindquist et al., 2008). However, non-carriers who have remained unaffected well past the family’s mean age at onset, a requirement for Alzforum’s definition of segregation (see Methods), have not been reported.

Clinical and family data
This mutation was first identified in an American kindred from the Midwest with at least 10 affected family members over four generations known as FTD004 (Hutton et al., 1998). The mutation was described as segregatinge with dementia and transmitted in an autosomal-dominant manner. The average age at onset was 55, ranging between 45 and 75 years. The clinical phenotype resembled AD and was characterized by memory loss and personality changes. At the age of 47, the proband developed a slowly progressing memory impairment followed by a parkinsonian gait. Like other members of his family, he had a protracted disease course, surviving nearly 30 years after symptom onset. This kindred was of Danish ancestry (Reed et al., 1997).

The R406W mutation was subsequently detected in a family from the Netherlands (Dutch4) described as having a slowly progressing dementia (van Swieten et al., 1999). The reported pedigree included six affected individuals spanning three generations. Onset started with memory loss and personality changes. Language deficits occurred in some family members, with two individuals becoming mute eight to 10 years after onset. The mean age at onset in this family was 59.2 years, with mean duration of 12.7 years.

A Belgian family (Family AD/G) with this MAPT mutation was reported a few years later (Rademakers et al., 2003) and followed across 18 years (Gossye et al., 2023). In the original report, the family was described as expressing a clinical phenotype consistent with AD. The mutation was present in four affected family members and 13 of 24 at-risk family members, with one affected individual not carrying the mutation. Memory impairment was the first symptom, followed by behavior and speech problems. Affected individuals received diagnoses of AD, or in some cases, unspecified dementia. The average age of onset in this kindred was 58.7 years (range: 54 to 65 years), with an average duration of 13.7 years (range: 7 to 22 years). In this family, co-existing mutations in PSEN1, PSEN2, and exons 16 and 17 of APP were excluded.

In the follow-up study (Gossye et al., 2023), additional Belgian carriers were identified from an FTD cohort (four carriers) and an AD cohort (three carriers). Shared haplotypes suggested they were all descendants of a common ancestor (Gossye et al., 2023), while haplotype analyses of families with Dutch and Danish ancestries showed that the mutation likely arose separately in the three European countries (Rademakers et al., 2003). The spectrum of phenotypes reported in the follow-up study ranged from typical bvFTD to clinical AD, based on cerebrospinal fluid biomarkers and amyloid PET scans. Some patients had phenotypes with FTD/AD overlap. Common neuropsychiatric symptoms, such as disinhibition and aggressiveness, occurred in all FTD cases and 58 percent of clinical AD patients, while memory impairment affected 89 percent of FTD patients and all clinical AD patients. Median age at death was lower in patients with FTD (68 years) compared to those with clinical AD (79 years). 

Additional families and individual carriers described in the literature include European families from Sweden (Passant et al., 2004; Ostojic et al., 2004) and Denmark (Lindquist et al., 2008), as well as two unrelated British carriers (Wood et al., 2016). Moreover, American individual carriers (Wojtas et al., 2012) and an American family (Carney et al., 2013) have been described, as well as, a carrier of Latin American origin (Hirschbichler et al., 2015). The mutation has also been identified in Asian families, including three Japanese families with a likely common ancestor (Ikeuchi et al., 2008; Ikeuchi et al., 2011), an Iranian family (Basiri et al., 2015; Behnam et al., 2015), as well as a Chinese individual (Han et al., 2020).

People homozygous for the R406W mutation have been identified. Two homozygous brothers from Iran had early onset FTD with symptoms appearing in their 30s (Basiri et al., 2015; Behnam et al., 2015). It is not clear if they had an earlier onset or more severe disease than affected heterozygotes in their family. Another homozygous individual also showed symptoms in his 30s, starting with agitation and personality changes. He then developed memory impairment, delusions, and social disinhibition, leading to a diagnosis of bv FTD. He also developed parkinsonism. Of note, his symptoms appeared nearly two decades earlier than family members who were presumed heterozygotes (Ng et al., 2015).

This variant was reported in the gnomAD variant database at a frequency of 0.000015 including 24 heterozygotes, all of European ancestry (gnomAD v4.1.0, Jan 2025).

Neuropathology
Neuropathological findings have been reported for several R406W carriers from multiple countries, including the United States (e.g., Reed et al., 1997; Mott et al., 2005; Qi et al., 2025), Holland (e.g., van Swieten et al., 1999; Rosso et al., 2000; de Silva et al., 2006), Japan (e.g., Miyasaka et al., 2001; Saito et al., 2002; Ishida et al., 2015), Belgium (Gossye et al., 2023), Sweden (Ygland et al., 2018), the UK (Wood et al., 2016; Qi et al., 2025), and Denmark (e.g., Lindquist et al., 2008).

In general, postmortem analyses showed bilateral temporal atrophy with neuronal loss, ballooned neurons, and gliosis. In a study using machine learning to characterize patterns of regional atrophy in MAPT-associated FTD, all R406W carriers (seven) were assigned to the temporal subtype which was associated with memory loss and characterized by early stage atrophy in the hippocampus, amygdala, medial and lateral temporal cortex, and temporal pole, as well as anterior and posterior insular cortex (Young et al., 2021). Consistent with these findings, magnetic resonance imaging studies have revealed that R406W carriers often lack the frontal gray and white matter atrophy typical of other MAPT mutation subtypes, and instead have mostly bilateral temporal and insular atrophy (Chu et al., 2020; Ikeuchi et al., 2011). Indeed, even at presymptomatic stages, tau accumulation has been detected in medial and temporal lobes (Wolters et al., 2021; Jones et al., 2018).

Also characteristic are abundant hyperphosphorylated tau-positive inclusions, including widespread neurofibrillary tangles throughout the cortex and the hippocampus, and to a lesser extent in brainstem nuclei (e.g., Reed et al., 1997; Miyasaka et al., 2001; Qi et al., 2025). In neurons, tau aggregates include neurofibrillary tangles, and sometimes, Pick body-like inclusions. In later stages of disease, “ghost tangles”—extracellular inclusions left behind after neurons die—have been observed, similar to those seen in AD. Tau fibrils in astrocytes result in tufted astrocytes, thorn-shaped astrocytes, and astrocytic plaques, and in oligodendrocytes coiled bodies are observed. Filaments can be composed exclusively of mutant tau, or of both the mutant and wildtype protein (Miyasaka et al., 2001; Qi et al., 2025). Although Aβ deposits have been reported (e.g., Ishida et al., 2015), they are generally sparse or absent (e.g., Reed et al., 1997; Mott et al., 2005; Saito et al., 2002; Ygland et al., 2018).

Of note, cryo-electron microscopic analysis of the structures of tau filaments from the brains of two R406W carriers revealed the same fold adopted by paired helical tau filaments in AD (Qi et al., 2025; March 2025 news). These filaments were found in both neurons and astrocytes. Consistent with this finding, multiple imaging studies have shown that tau PET tracers that detect AD-associated tau pathology consistently detect tau in R406W carrier brains (e.g., Smith et al., 2016; Jones et al., 2018; Leuzy et al., 2020; Wolters et al., 2021; Levy et al., 2022; Santillo et al., 2023). Also, R406W carriers have AD-like elevations of the ptau217/tauT217 ratio in CSF (Sato et al., 2021), and of the microtubule-binding region (MTBR) containing residue 243 (MTBR-tau243) which has been proposed as a biomarker for insoluble tau aggregates in AD (Horie et al., 2023).

Tau inclusions are made of all six tau isoforms (van Swieten et al., 1999), with both three-repeat (3R) and four-repeat (4R) tau paired-helical filamentous tau aggregates that are hyperphosphorylated like those observed in AD (de Silva et al., 2006; Qi et al., 2025). Some studies, however, have identified carriers with predominantly 3R (Gossye et al., 2023) or 4R (Ygland et al., 2018) tauopathy. Mutant tau appears to co-deposit with wildtype tau (e.g., Miyasaka et al., 2001; Qi et al., 2025), but in at least one case, wildtype filaments were absent (Qi et al., 2025). The latter study also reported TMEM106B filaments in both R406W carriers.

Neuropathological heterogeneity extends even further. In one of the two cases examined in the cryo-EM study, for example, tau filaments with a fold similar to that found in chronic traumatic encephalopathy (CTE) were observed (Qi et al., 2025; March 2025 news). Also, the site of neuropathology—frontal cortex, temporal cortex, putamen, globus pallidus, substantia innominate, amygdala, thalamus, hippocampus, entorhinal cortex, raphe nucleus, and/or pontine nucleus—varies between individual carriers (see Ghetti et al., 2015 for review). Right side predominance of temporal atrophy has been reported in some cases (e.g., Wood et al., 2016; Ulugut et al., 2021), and in others, neuropathological similarities with progressive supranuclear palsy (Reed et al., 1997; Ygland et al., 2018).

Biological Effect
The R406W mutation alters a highly conserved residue near the C-terminus of the tau protein, resulting in the change from a positively charged, polar side chain to a neutral, aromatic, and highly hydrophobic side chain.

Aggregation
R406W tau gives rise to tau filaments with the AD fold, a back-to-back C-shaped structure that was first described in tau fibrils extracted from an AD brain (March 2025 news; Qi et al., 2025). The filament cores are composed of two identical protofilaments spanning amino acids 306 to 378, which adopt a combined cross-β/β-helix structure (Fitzpatrick et al., 2017). Oligomers of R406W tau appear to be distinct from oligomers of other tau mutants, as well as wildtype tau, having a particularly high level of cross- β-sheet structure (Bhopatkar et al., 2024).

It is still unclear how R406W contributes to the formation of aggregates, however. Aggregation studies in vitro have yielded mixed results (see Strang et al., 2019 for review). Some studies have reported R406W enhances aggregation (Nacharaju et al., 1999; Barghorn et al., 2000; DeTure 2002), increases tau oligomerization (Maeda et al., 2018), and decreases the lag time of polymerization (in 2N and 0N isoforms; Mutreja et al., 2019). However, at the same time, several studies have found little or no effect on the extent (e.g., Mutreja et al., 2019; Bardai et al., 2018) and general profile of aggregate formation, R406W’s nucleation capacity (e.g., Guo et al., 2011; Aoyagi et al. 2007; Chang et al., 2008), and its ability to fuel filament extension (e.g., Chang et al., 2008) compared to wildtype tau. Experimental conditions may explain some of these discrepancies. For example, R406W does not appreciably influence the heparin-induced assembly of full-length tau filaments (Goedert et al., 1999) whose structure differs from those found in vivo with the AD-fold conformation (Zhang et al., 2019; Qi et al., 2025).

Because R406 lies outside the ordered cores of AD-fold tau filaments, it is unlikely the R406W substitution has a direct effect on aggregation (Qi et al., 2025). Instead, it may cause a structural change. As suggested in a preprint, R406W is expected to increase tau’s hydrophobicity and may increase the likelihood of a cis-proline amide bond forming at P405 (Ganguly et al., 2023 preprint; Ganguly et al., 2024). The kinking induced by such a bond could reduce the ability of the C-terminal domain to fold against the tubulin-binding domain and protect it from aggregation.

Whether and how phosphorylation plays a role in this, and/or other structural changes related to aggregation remains uncertain. As noted above, tau hyperphosphorylation is a hallmark of the neuropathology observed in R406W carriers, but experiments assessing the effects of R406W on tau phosphorylation and aggregation in cells and isolated proteins have yielded mixed results. While some have found a connection between enhanced phosphorylation and aggregation (e.g., Alonso et al., 2004; Alonso et al., 2010), others have reported reduced phosphorylation associated with aggregation (e.g., DeTure et al., 2002, Vogelsberg-Ragaglia et al., 2000). Moreover, it is possible that phosphorylation affects R406W aggregation indirectly, via effects on microtubule binding (see below). As suggested in one study, loss of the mutant’s protein ability to interact with microtubules may be necessary for aggregation (Qi et al., 2025).

Of note, R406W has also been reported to alter tau proteolysis, a disruption that may be modulated by phosphorylation (e.g., Yen et al., 1999; Vogelsberg-Ragaglia et al., 2000; Yanagi et al., 2009; Bardai et al., 2018; Nakamura et al., 2019).

Microtubule dynamics
Despite being outside the microtubule-binding repeat domains, several studies have found this mutation reduces both the ability of tau to bind microtubules (e.g., Hong et al., 1998; DeTure et al., 2000; Zhang et al., 2004; Xia et al., 2019) and microtubule assembly (e.g., Hong et al., 1998; Rizzu et al., 1999; Han et al., 2009; Sahara et al., 2000; Mutreja et al., 2019; for reviews see Strang et al., 2019 and Xia et al., 2019). However, results are mixed including some studies which have found little or no effect of R406W on microtubule binding (e.g., Barghorn et al., 2000; Vogelsberg-Ragaglia et al., 2000; Delobel et al., 2002) or microtubule assembly (e.g., Hasegawa et al., 1998; Dayanandan et al., 1999; DeTure et al., 2000; Bunker et al., 2006), particularly compared to other MAPT mutations such as V337M and P301L.

Several reasons may underlie these discrepancies, including small effects that might be difficult to detect in some experimental systems (e.g., Vogelsberg-Ragaglia et al., 2000, Hasegawa 1998, Dayanandan et al., 1999) and a dependence on the tau isoform studied (e.g., Mutreja et al., 2019).

There is also uncertainty about how this variant affects tau phosphorylation and its relationship to microtubule binding and assembly. Some studies have suggested that phosphorylation of the mutant protein reduces tau binding to microtubules (e.g., Pérez et al., 2000; Vanhelmont et al., 2010; Han et al., 2009) and this effect can be reversed by dephosphorylation (Krishnamurthy and Johnson 2004). However, several studies have reported reduced phosphorylation of R406W in vitro, with some studies suggesting that altered secondary structure induced by the mutation blocks phosphorylation (e.g., Vogelsberg-Ragaglia et al., 2000, Sakaue et al., 2005, Connell et al., 2001). It has also been proposed that the mutant’s altered ability to bind microtubules and its effects on microtubule dynamics interfere with normal phosphorylation and/or dephosphorylation (Matsumara et al., 1999; Sakaue et al., 2005; Yotsumoto et al., 2009). 

In general, in vitro studies have found R406W associated with reduced phosphorylation at T231 (e.g., Matsumara et al., 1999; Anderton et al., 2001; DeTure et al., 2002; Delobel et al., 2002), S396 and/or S404 (e.g., Matsumara et al., 1999; Pérez et al., 2000; Vogelsberg-Ragaglia et al., 2000; Delobel et al., 2002; DeTure et al., 2002; Tatebayashi et al., 2006; Han and Paudel, 2009; Yotsumoto et al., 2009; Vanhelmont et al., 2010; Kimura et al., 2016), and S409 (e.g., Vanhelmont et al., 2010), while increased phosphorylation has been reported at S202/T205 and S400. However, there are also reports of reduced phosphorylation at the S202/T205 sites (e.g., DeTure et al., 2002), and increased phosphorylation at S396/S404 (e.g., Lee et al., 2009; Alonso et al., 2004; Yanagi et al., 2009), as well as the gain of an additional phosphorylation site (Kimura et al., 2016) and alterations in dephosphorylation kinetics (e.g., Yotsumoto et al., 2009). Adding to this complex picture, the effects of R406W may vary across the multiple kinases and phosphatases that normally have access to each site. Moreover, the disruption of one phosphorylation site can affect phosphorylation at other sites (e.g., Tatebayashi et al., 2006).

Additional subcellular effects
Several studies have found R406W alters neuronal function, affecting axons, dendrites, calcium dynamics, and neurotransmitter receptors. Disruptions of axonal transport, for example, have been reported in assays using isolated proteins in vitro (Yu et al., 2014), a Drosophila model system (Butzlaff et al., 2015), in tracer experiments in transgenic mice (Zhang et al., 2004), and in cortical neurons derived from induced pluripotent stem cells (iPSCs) (Sep 2019 news; Nakamura et al., 2019). In addition, in this same iPSC study, mutant tau was found mislocalized to dendrites, and in a study in lamprey neurons, the mutant protein was enriched in proximal dendrites (Lee et al., 2009). Alterations in synaptic proteins and functions have also been reported, including dysregulation of synaptic calcium dynamics in iPSC-derived neurons (Imamura et al., 2016; Minaya et al., 2023), as well as reductions in GABA receptors and disruptions of glutamatergic (Jiang et al., 2018; Dec 2018 news; Minaya et al., 2023) and possibly serotonergic (Egashira et al., 2005) synaptic function.

Lysosomal and autophagic functions also appear to be disrupted by R406W tau. In iPSC-derived neurons, for example, morphological and functional deficits were observed in the lysosomal pathway (Mahali et al., 2022), while upregulation of lysosomal pathway genes was identified in another study of mutant iPSC neurons (Minaya et al., 2023). In flies, increases in the activation of the unfolded protein response and autophagy were reported (Bardai et al., 2018). In this study, increased activation of caspases and JNK signaling was also identified, suggesting increased apoptosis and oxidative stress. Moreover, GRAM Domain Containing 1B (GRAMD1B)--a regulator of lipid homeostasis, autophagic flux and phosphorylated tau—was increased in excitatory neurons of human neural organoids carrying R406W (Acosta Ingram et al., 2025). 

Interestingly, R406W has also been associated with disruptions in tau-membrane interactions (Gauthier-Kemper et al., 2011) and in the bundling and accumulation of filamentous actin (Fulga et al., 2007; Jan 2007 news).

Moreover, in Drosophila, R406W tau was implicated in decreased tension on the nuclear cytoskeleton (Sohn et al., 2023), a reduction in nuclear calcium and transcription factor CREB activity (Mahoney et al., 2020), and chromatin relaxation resulting in aberrant gene expression (Frost et al., 2014).

Proteome and transcriptome analyses have been performed in Drosophila expressing human R406W or wildtype human tau pan-neuronally (Mangleburg et al., 2020), mutant iPSC neurons (Minaya et al., 2023), and samples of the insular cortex of two R406W carriers (Minaya et al., 2023). Downregulation of long noncoding RNAs (lncRNAs) may underlie some of the changes seen in the altered expression profiles (Bhagat et al., 2023; Sep 2023 news).

Of note, although tau is expressed mostly in neurons, R406W tau appears to affect glial cells as well. Like neurons, astrocytes appear to develop tau inclusions with the AD fold (Qi et al., 2025). Moreover, in iPSC-derived cerebral organoids, R406W increased cholesterol production in astrocytes (Glasauer et al., 2022; Sep 2022 news) and, in Drosphila, mutant tau in glia disrupted these cells’ ability to form lipid droplets that neutralize toxic lipids secreted by stressed neurons (Goodman et al., 2024; Oct 2024 news). Also in fruit flies, mutant tau was reported to activate retrotransposons, boosting transcription of dsRNA, possibly contributing to inflammation and neurodegeneration (Jan 2023 news; Ochoa et al., 2023).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (27), suggesting a deleterious effect (CADD v1.7, April 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Likely Pathogenic*

*Clinical phenotypes varied between carriers.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Research Models

The tau R406W mutation has been introduced into several rodent models of Alzheimer's disease, alone or in combination with other mutations, because of its ability to significantly reduce the age of onset of AD-like symptoms and neuropathology. Examples include RW Tg mice, Tau R406W transgenic mice, PLB1-triple (hAPP/hTau/hPS1) mice, and TMHT (Thy-1 mutated human tau) mice. 

In addition, several iPSC lines from R406W carriers, including a homozygous line, as well as isogenic lines corrected to wildtype, have been generated (e.g., Oct 2019 news; Karch et al., 2019; Imamura et al., 2016; Jiang et al., 2018; Rasmussen et al., 2016; Nimsanor et al., 2016a; Nimsanor et al., 2016b). Also, an iPSC line from an individual of African ancestry engineered to carry the R406W mutation is available from the African Somatic and Stem Cell Bank (Maina et al., 2025). Human organoids derived from iPSCs have also been created (e.g., Glasauer et al., 2022; Acosta Ingram et al., 2025).

Lastly, invertebrate models, including Drosophila (e.g., Butzlaff et al., 2015; Haddadi et al., 2016; Ochoa et al., 2023) and C. elegans (e.g., Miyasaka et al., 2016), have also been used as tools to study this mutation.

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References

Research Models Citations

1. RW Tg mice
2. Tau R406W transgenic
3. PLB1-triple (hAPP/hTau/hPS1)
4. TMHT (Thy-1 mutated human tau)

News Citations

1. Introducing: iPSC Collection from Tauopathy Patients 23 Oct 2019
2. Filling in the Family Tree: AD, CTE Folds Spotted in Other Tauopathies 27 Mar 2025
3. Mutant Tau Stiffens Axon Cytoskeleton Near Soma 20 Sep 2019
4. Stem Cell Model Nails Link Between Tauopathy and GABAergic Dysfunction 21 Dec 2018
5. New Takes on Tau: Does It Stabilize Actin, Flag Neurogenesis? 4 Jan 2007
6. Missing ‘Lnc’? Long Noncoding RNAs Bind Tau, Tame Stress Granules 22 Sep 2023
7. Organoids Implicate Cholesterol Dysregulation in Tau Pathology 16 Sep 2022
8. New Role for Tau: Making Lipid Droplets in Glia? 22 Oct 2024
9. Does Double-Stranded RNA From Jumping Genes Mediate Tau Toxicity? 18 Jan 2023

Book page Citations

1. Methods 6 Feb 2018

Paper Citations

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