Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46010324 T>G
Position: (GRCh37/hg19):Chr17:44087690 T>G
dbSNP ID: rs63750756
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Missense
Codon Change: AAT to AAG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10
Research Models: 1

Findings

Among MAPT mutations, the N279K is one of the most frequent causes of familial frontotemporal dementia (FTD). The mutation has been identified in more than a dozen families worldwide, with data suggesting autosomal dominant inheritance with full penetrance. N297K is a very rare variant in the general population; indeed, it is absent from the gnomAD variant database (v.4.1.0, Apr 2024). Phenotypic presentation varies, but affected individuals generally develop symptoms of dementia, parkinsonism, and progressive supranuclear palsy (PSP). Individuals with the N279K mutation typically have a parkinsonism-predominant phenotype, consistent with the pallido-ponto-nigral degeneration (PPND) subtype of FTD. Personality changes, behavioral changes, and dementia also occur, but they may be less prominent and/or seen later in the course of the disease (Tsuboi et al., 2002).

One of the largest N279K kindreds is from North America, known as the PPND family, and has been longitudinally studied since 1987 (Caviness et al., 2003). This family comprises at least 57 affected people across eight generations. Individuals in this family develop a particularly aggressive form of disease characterized by progressive parkinsonism with dystonia, rigidity, bradykinesia, postural instability, dementia, ocular motility abnormalities, pyramidal tract dysfunction, frontal lobe release signs, personality changes, perseverative vocalizations, and urinary incontinence (Wszolek et al., 1992; Markopoulou et al., 2016). Olfactory dysfunction also appears prior to symptom onset, and develops in an age-dependent and irreversible manner; however, severe olfactory dysfunction is not fully penetrant (Markopoulou et al., 2016; Arvanitakis et al., 2007). Sleep impairment is also prominent in affected N279K-carrying individuals, as demonstrated by a reduced total sleep time and increased sleep latency, among other parameters, compared to unaffected family members (Spector et al., 2011). Mutation carriers in the PPND family have an average age of onset of 43 years and disease duration of 8 years (Markopoulou et al., 2016).

The N279K mutation has also been detected throughout the world beyond North America, including in more than 10 Japanese families (Arima et al., 2000; Yasuda et al. 1999; Tsuboi et al., 2002; Ogaki et al., 2011; Ogaki et al., 2012; Ikeda et al., 2019; Oka et al., 2020; Shimura et al., 2005). In at least three of these families, the clinical syndromes resembled PSP (Ogaki et al., 2011; Ogaki et al., 2012). In one of the largest of these families, family B, the reported pedigree indicates nine individuals over three generations affected by parkinsonism (n=7) or dementia with parkinsonism (n=2). The N279K mutation was present in three affected carriers (two with parkinsonism with dementia, one with parkinsonism without dementia) and apparently absent in a relative who remained healthy into her 60s, well past the family's mean age of onset which ranged from 42 to 46 years of age. Although the authors imply this latter individual did not carry the mutation, her genotype was not explicitly reported. All three affected carriers had parkinsonism as the initial symptom. Symptoms included bradykinesia, rigidity, postural tremors, gaze palsy, and motor impairments.

In another family, two individuals with parkinsonism- and one with dementia-predominant disease were reported, all of whom first presented symptoms early in the fourth decade (Oka et al., 2020). Of note, the patient with dementia-predominant disease clinically presented with bvFTD, and PSP was pathologically confirmed at death, 6 years after onset. All three individuals exhibited personality changes as well as bradykinesia, rigidity, and postural instability. Although they had affected family members, their mutational status had not been confirmed.

The N279K mutation was also identified in a large Chinese family with autosomal-dominant parkinsonism (Yang et al., 2015). The reported pedigree shows 21 affected family members over four generations. Prior to the identification of their mutation, affected family members were misdiagnosed with Parkinson’s disease due to their prominent parkinsonian symptoms (e.g., rigidity, hypokinesia, postural instability, and tremor). The diagnosis was later corrected to FTD with parkinsonian features. Disease in this family developed early (onset ranged from 39 to 48 years of age), and progressed rapidly (duration varied from 4 to 11 years). In addition to parkinsonism, personality changes were prominent early in the disease, including apathy, irritability, and disinhibition, and worsened as the disease progressed. Some family members were affected by supranuclear palsy, and dementia was common, although cognitive decline occurred subsequent to parkinsonism. Thirty-nine family members were genotyped (five affected, 34 unaffected) and the N279K mutation appeared to segregate with the presence of disease, but the ages of the unaffected non-carriers were not reported.

Beyond this extensive family study, N279K has been identified in others from China (Tang et al., 2016, Wu et al., 2018, Nan et al., 2024). Of note, segregation with disease was described in at least one of these studies in which a female patient from a FTD-parkinsonism family was found to carry N279K (Tang et al., 2016). She was initially misdiagnosed with Parkinson's disease based on tremor, bradykinesia, and rigidity at age 40, but by her second admission at age 44, she exhibited behavioral changes and increased irritability, leading to a revised diagnosis of FTD-parkinsonism. Two of her three siblings were affected, including a deceased brother and a living sister with similar symptoms who also carries N279K. At the time of publication, her other living sister and their father were unaffected and did not carry the mutation.

N279K has also been detected in South America. A 45-year-old Brazilian male was described with the behavioral variant of FTD (bvFTD) and PSP characterized by axial-predominant parkinsonian features and eye-movement abnormalities (Takada et al., 2016). This individual had four siblings who had died due to disease suggestive of PSP.

Reports of patients carrying N279K have also been described in Europe. An Irish 36-year-old female patient with the N279K mutation was diagnosed with PPND after being misdiagnosed with Parkinson’s disease by three specialists (O’Dowd et al., 2012). Her father (genetics not reported) had been diagnosed with Parkinson’s disease, although he had a poor response to levodopa therapy. Her initial symptoms included slowness of movement while swimming, reduced facial expressions, and insomnia, but by 44 years of age she required full nursing care and her symptoms included akinesia, aphasia, apraxia of eyelid opening, dysphagia, and cachexia. Her 42-year-old sister, also an N279K carrier, also exhibited a lack of facial expression. Italian (Soliveri et al., 2003) and French (Delisle et al., 1999) families with the N279K mutation have also been reported and include patients with dementia and PSP.

In a large international, retrospective cohort study, 44 individuals from 17 families with the N279K mutation were identified in the Frontotemporal Dementia Prevention Initiative and the published literature, including 22 with parkinsonism and 12 with dementia not otherwise specified (Moore et al., 2020). The mean age of disease onset was 43.8 years (n=36), the mean age at death was 52.4 years (n=38), and the mean disease duration was 6.5 years (n=31). No other information is provided about these families, and it is unclear whether it overlaps with the families described above. Of note, this study included both confirmed mutation carriers, as well as family members who were assumed to be carriers based on their clinical phenotype.

In sum, N279K is a common mutation underlying familial FTD, characterized by early onset and rapid progression. It presents globally across groups of diverse ancestries, with a predominant parkinsonism phenotype, and is often initially misdiagnosed as Parkinson's disease.

Neuropathology

Autopsy findings have revealed severe neuronal loss with gliosis in the frontal and temporal lobes, substantia nigra, pontine tegmentum, and globus pallidus, with some loss also in the caudate and putamen (Slowinski et al., 2007; Oka et al., 2020). MRI of a female Chinese Han patient also revealed bilateral frontal and temporal lobe atrophy (Nan et al., 2024). Notably absent from patients with the N279K mutation are plaques, tangles, Lewy bodies, and amyloid bodies (Wszolek et al., 1992).

Nonetheless, although tau tangles are not typical, they do occur (Al-Dalahmah et al., 2024), and other types of tau inclusions have been described in neurons and glia in a variety of brain regions, including the cortex, basal ganglia, hippocampus, brain-stem nucleipons, and spinal cord white matter (Slowinski et al., 2007; Oka et al., 2020). Tau pathology includes pretangles, threads, grain-like granules, and coiled bodies (Slowinski et al., 2007). Moreover, tau pathology was also present in sleep-related brain regions, which correlated with the sleep dysfunction observed in some affected individuals (Spector et al., 2011). Inclusions consisted primarily of four-repeat (4R), not three-repeat (3R), isoforms of tau, consistent with PSP (Delisle et al., 1999; Ogaki et al., 2012). In some cases, substantial tau deposition was also observed in the medial temporal cortices and upper and lower motor neurons with accompanying corticospinal tract degeneration (Arima et al., 2000).

As the disease progresses from preclinical to symptomatic stages, imaging studies have provided insights into brain changes associated with the N279K mutation. Three siblings from the PPND kindred were examined at different disease stages (preclinical, age 43; prodromal, age 45; and mild FTD, age 51) for striatal dopamine transporter (DAT) binding using 123I-FP-CIT SPECT, and scores were inversely correlated with disease progression (Miyagawa et al., 2024). Notably, DAT expression was found to be reduced already in presymptomatic stages, which is in line with a finding in presymptomatic mutation carriers from a Chinese Han family using a different radioligand to detect DAT (Wu et al., 2018). All PPND family siblings eventually developed bvFTD and died between the ages of 52 and 55 (Miyagawa et al., 2024). At autopsy, frontotemporal degeneration was observed in all three individuals, showing extensive neuronal and glial 4R tau pathology along with neuronal loss and gliosis in the substantia nigra. An earlier study using the same imaging method to assess DAT had similar findings, showing that two affected N279K carriers who were diagnosed with bvFTD with parkinsonism had lower DAT density in the caudate nucleus and anterior putamen compared to control individuals and also when compared to patients with Parkinson’s disease (Takeshige et al., 2018).

Tau pathology associated with N279K appears to be distinct from that seen in Alzheimer's disease (AD). The PET imaging ligand 18F-AV-1451 (also known as flortaucipir or T807) was used to evaluate AD–type tau aggregates in the temporal pole in five individuals with the N279K mutation, including one asymptomatic participant and four participants with FTD with parkinsonism and PPND (Jones et al., 2018). While the signal was lower than in patients with AD and lower than in those with MAPT mutations outside of exon 10, it was similar to that in clinically healthy individuals.

The role of microglial activation in the early stages of disease has been examined. In three presymptomatic N279K gene carriers (aged 38-41 years) from the large PPND family, increased microglial activation was detected in the frontal, occipital, and posterior cingulate cortices by PET imaging compared to healthy controls (Miyoshi et al., 2010). Low dopamine synthesis rates were also observed by PET in the putamen, and MRI further revealed hippocampal atrophy.

Metabolic changes in the brain are another aspect explored through imaging in N279K mutation carriers. In the Irish patient with PPND described above, FDG-PET revealed hypometabolism in the mesial temporal lobes and increased T2 signal on fluid attenuated inversion recovery MRI in the same regions 5 years after symptom onset (O’Dowd et al., 2012).

In sum, neuropathological studies of patients carrying the N279K mutation reveal a pattern of severe neuronal loss, distinctive 4R tau pathology without typical AD features, and notable changes in brain metabolism and microglial activation, as evidenced by various imaging techniques across different disease stages.

Biological Effect

Tau splicing
N279K is located in an exonic splicing enhancer (D'Souza et al., 1999; Rodriguez-Martin et al., 2009). Similar to many intronic mutations in MAPT, the N279K mutation affects exon 10 splicing in vitro, resulting in more frequent incorporation of exon 10 into transcripts and the relative over-production of the 4R tau isoform (Delisle et al., 1999; Hasegawa et al., 1999). Indeed, in frontal cortex and cerebellum samples from patients with PPND, the 4R-to-3R ratio was greater than that in control brain samples (Hong et al., 1998). This occurs through the strengthening of a poly-purine positive cis-element in exon 10, which promotes greater exon 10 inclusion during splicing (Hutton et al., 2001). Namely, the splicing factors Tra2β and SF2/ASF have a stronger affinity to the exonic splicing enhancer in the presence of N279K (Jiang et al., 2003; Kondo et al., 2004; D’Souza and Schellenberg et al., 2006; Rodriguez-Martin et al., 2009). N279K may also lead to greater exon 10 inclusion by reducing binding to the splicing regulator SRp30c, which under wild-type conditions inhibits splicing of exon 10 (Wang et al., 2005).

To examine the effects of this mutation on splicing, induced pluripotent stem cells (iPSCs) have been generated from fibroblasts of affected N279K carriers. iPSC-derived neuronal stem cells carrying the N279K mutation also produce more 4R tau than 3R tau (Wren et al., 2015); this was also replicated in another model of iPSC-derived neurons (Ehrlich et al., 2015; Al-Dalahmah et al., 2024).

Tau aggregation
Hexapeptide motifs within the tau protein are important for tau aggregation and conformation, and several are found in the microtubule binding region, including the PHF6∗ motif (VQIINK), which coincides with the location of N279K (Karikari et al., 2019; Karikari et al., 2020). These motifs regulate aggregation through tau-tau interactions, which facilitate a shift from a random coil to a cross β-sheet structure. The K18 fragment, which encompasses several hexapeptide motifs, was modified to express the N279K mutation in one study to evaluate tau conformation and aggregation in vitro (Karikari et al., 2019). Transmission electron microscopy findings showed that while the filament length did not differ from those produced by wild-type K18 fragments, N279K K18 fragments exhibited wider filaments. This indicated that the morphology of tau aggregates can be affected by the N279K mutation. Moreover, the conformation of N279K K18 fragments differed from that seen in WT K18 based on distinct immunostaining patterns to antibodies detecting different epitopes.

Despite these alterations in the structure of tau aggregates, N279K does not seem to fuel tau aggregation per se. In N279K-expressing HEK293T cells that were exposed to preformed wild-type K18 tau fibrils, which are aggregation-prone, tau did not accumulate, indicating a lack of seeding and tau inclusion formation (Strang et al., 2018). In fact, in one in vitro study using thioflavin S dye fluorescence to measure aggregation, an N279K tau fragment was found to aggregate at a rate even slower than that of wild-type tau (Yao et al., 2003); this was also true for mutated K18 fragments in another study, but not for full-length tau (Barghorn et al., 2000).

Tau turnover
This mutation also appears to disrupt tau turnover. In silico analyses predicted it diminishes cathepsin cleavage which was confirmed using in vitro protease assays (Sampognaro et al., 2023). Consistent with these findings, the lysosomal degradation of mutant tau in neuronal-like SH-SY5Y cells, as well as in neurons derived from iPSCs, was reduced.

In addition, when N279K K18 tau oligomers were applied to SH-SY5Y cells, they were internalized through endocytosis to a greater extent than wild-type K18 oligomers (Karikari et al., 2019). Nonetheless, application of mutant oligomers did not affect cell viability as measured by lactate dehydrogenase release, a proxy for cytotoxicity.

Tau localization
Tau is usually localized to axons and associated with microtubules, although it can be found in other cellular compartments including the plasma membrane and nucleus. In COS-7 cells carrying the N279K mutation, tau was found to localize in the nucleus to a greater extent than in wild-type cells using confocal microscopy and subcellular fractitionation plus western blot methods (Ritter et al., 2018). Despite this change in the subcellular distribution of mutant tau, cell viability remained the same. In iPSC-derived neurons, however, somatodendritic redistribution of phosphorylated tau was not observed, but neurite extension was impaired compared to control cells (Ehrlich et al., 2015). In another study of human iPSC-derived neurons, exogenous application of N279K mutant K18 oligomers, which led to internalization of tau, resulted in tau colocalization with the nuclear protein nucleolin; interestingly, this colocalization was generally not observed when SH-SY5Y cell were used (Karikari et al., 2019).

Tau phosphorylation
Tau phosphorylation was assessed in COS-7 cells, and compared to wild-type–expressing cells, those with the N279K mutation had increased phosphorylation at the AT8 epitope (S202, T205; Ritter et al., 2018). This hyperphosphorylation of AT8, as well as AT100 (T212, S214), has also been observed in N279K iPSC-derived neurons (Iovino et al., 2015). Increased tau phosphorylation and fragmentation was also observed in another study of iPSC-derived neurons from N279K carriers (Ehrlich et al., 2015; Al-Dalahmah et al., 2024). Corresponding to the increased phosphorylation, one study found a reduction in the binding affinity of N279K tau for protein phosphatase 2A, a major phosphatase of tau, via coimmunoprecipitation of transfected mouse NIH 3T3 fibroblasts (Goedert et al., 2000).

Protein phosphorylation
Apart from tau phosphorylation, protein phosphorylation more broadly is affected by the N279K mutation. In a proteomic analysis of the hippocampus in an N279K-expressing transgenic mouse model, phosphorylation of calreticulin and tubulin β4 was increased, while decreases were seen in other proteins, including heat shock cognate 71 kDa protein and tubulin β2 (Takano et al., 2009).

Microtubule binding
Across multiple studies, microtubule-binding assays revealed that recombinant N279K tau did not differ from wild-type tau in microtubule assembly, including lag time, rate of assembly, or maximal amount of microtubule polymers formed (D'Souza et al., 1999; also see Hasegawa et al., 1999 and Hong et al., 1998). However, one report found that N279K mutant tau had reduced microtubule assembly and binding compared with wild-type tau, possibly because the recombinant preparation (htau40) used in this study (i.e., the full-length tau) may have differed from those used in the other studies (Barghorn et al., 2000).

Metabolic abnormalities
Several lines of evidence suggest that the N279K mutation is associated with metabolic dysfunction. In a study using liquid chromatography–mass spectrometry, metabolic abnormalities were found in two lines of iPSC-derived human dopamine neurons carrying the N279K mutation compared to two wild-type cell lines, as observed by an increased abundance of oxidized phospholipids, suggesting that the mutation is associated with increased oxidative stress (Bradford et al., 2024). This is further supported by molecular assays demonstrating increased vulnerability to oxidative stress and activation of the unfolded protein response in iPSC-derived neurons from patients with the N279K mutation (Ehrlich et al., 2015; Al-Dalahmah et al., 2024). Moreover, using mass spectrometry and metabolomics analyses, higher levels of ATP were observed in these neurons as well as dysregulation in the mitochondrial electron transport chain, pyruvate metabolism, and amino acid metabolism (Al-Dalahmah et al., 2024). Extending these observations, in human iPSC–derived glutamatergic cortical neurons, mass spectrometry revealed that levels of proteins related to reactive oxygen species (ROS) regulation were increased in N279K cells versus controls, suggesting the involvement of oxidative stress pathways (Korn et al., 2023). This was further corroborated using live cell imaging, which showed that the rate of ROS production was higher in mutant cells. Crucially, this study showed these changes in neuronal oxidative stress were also associated with higher rates of cell death and increased expression of apoptosis markers (Korn et al., 2023).

The impact of the N279K mutation on cellular stress and apoptosis has been further explored in different model systems. For instance, in rat hippocampal neurons, transfection of a fragmented tau (tau151-421) carrying the N279K mutation potentiated apoptosis, but when the full-length N279K tau was transfected, no differences in apoptotic cells were seen compared to wild-type tau (Fasulo et al., 2005). Nonetheless, another report demonstrated that SH-SY5Y cells transfected with N279K tau were more vulnerable to apoptosis following serum withdrawal than those transfected with wild-type tau, seemingly through disrupted calcium homestasis (Furukawa et al., 2000). In addition, iPSC-derived neural stem cells show signs of cellular stress, including the accumulation of stress granules and vesicle trafficking deficits (Wren et al., 2015). Also of note, an N279K mouse model exhibited increased activated caspase-3 immunoreactivity compared to non-transgenic controls in neurons and astrocytes throughout the brain, pointing to the presence of ongoing apoptosis as a consequence of the mutation (Dawson et al., 2007). Together, these findings underscore N279K’s role in inducing significant metabolic disruptions, particularly through oxidative stress, which may contribute to the neurodegenerative processes observed in affected individuals.

Mitochondrial dysfunction
In human iPSC–derived glutamatergic cortical neurons, mitochondrial hyperpolarization, reduced mitochondrial mass, and increased mitochondrial fission were observed compared to a control line (Korn et al., 2023). Moreover, iPSC-derived neurons from patients with the N279K mutation exhibited impaired mitophagy and altered mitochondrial function (Al-Dalahmah et al., 2024). For example, compared to the control cell line, N279K-positive iPSC-derived neurons had an increased basal oxygen consumption rate. Another study using iPSC-derived neurons from an N279K carrier found that anterograde mitochondrial axonal transport was impaired compared to that in control cells (Iovino et al., 2015).

Astrocytic dysfunction
Astrocyte function was examined in an iPSC model of neural progenitor cells derived from a patient carrying the N279K mutation (Hallmann et al., 2017). While astrocyte differentiation per se was not perturbed, the astrocytes were larger and expressed greater levels of the 4R isoform of tau. Moreover, these iPSC-derived astrocytes were more vulnerable to oxidative stress as determined by the increase in cell death and lactate dehydrogenase release following rotenone application, as well as an increase in protein ubiquitination based on western blot analysis, pointing to altered protein degradation. Mutant iPSC-derived astrocytes also imparted dysfunction to previously healthy neurons in co-culture settings, namely an increase in vulnerability to oxidative stress, indicating the potential of the N279K mutation to induce non-cell autonomous effects.

Gene expression alterations
Investigations into the molecular mechanisms of the N279K mutation have included analyses of gene expression alterations. For instance, substantia nigra samples from patients carrying the N279K mutation were assessed via RNA microarrays (Al-Dalahmah et al., 2024). Differential expression was observed in genes related to microglia, spliceosome, and immune activation pathways. This study also conducted an in-depth analysis using single nucleus RNA sequencing to reveal cell type–specific alterations in gene expression compared to control samples.

Microarray has also been used to evaluate the transcriptome of iPSC-derived neurons from patients with the N279K mutation (Ehrlich et al., 2015). Gene expression profiles were found to be altered (e.g., increased expression of LOC100128252 and MAGEH1) compared to control cells, and these changes were also found in post-mortem samples from patients with FTD.

Moreover, in the iPSC-derived N279K astrocytes introduced above, transcriptome analysis revealed disease-associated changes when compared to control iPSC-derived astrocytes (Hallmann et al., 2017). Functional annotation uncovered that affected genes were related to plasma membrane, multicellular organism development, neurological system processes, and synaptic organization and transmission.

Several in silico algorithms, including Mutation Taster, SIFT, Provean, and PolyPhen-2, have predicted this variant is damaging (Nan et al., 2024). Moreover, its PHRED-scaled CADD score which integrates diverse information in silico, was above 20 (26.5), suggesting a deleterious effect.

Research Models

To explore the effects of the N279K mutation, several research models have been developed. A transgenic mouse model overexpressing a human tau with the N279K mutation was created to investigate clinical and neuropathological outcomes (Taniguchi et al., 2005; Takano et al., 2009; Takenokuchi et al., 2010; Chiba et al., 2012). Building on this, another transgenic model using a human tau minigene carrying N279K was developed to study exon 10 splicing (Dawson et al., 2007; Schoch et al., 2016; Jul 2016 news). More recently, the MAPT(H1.0*N279K)-GR mouse model was introduced, where the mouse Mapt-containing region is replaced with the mutated human H1 haplotype carrying the N279K mutation (Benzow et al., 2024; Nov 2022 news).

Moving to human cell models, several iPSC lines have been established from patients with the N279K mutation, allowing for detailed mechanistic studies at the cellular and molecular levels (Ehrlich et al., 2015; Iovino et al., 2015; Wren et al., 2015; Korn et al., 2023; Al-Dalahmah et al., 2024; Grigor’eva et al., 2024). These have been differentiated into neurons, as well as astrocytes (e.g., Hallmann et al., 2017), and genetically modified to express biosensor transgenes (Nadtochy et al., 2025). Additionally, N279K mutant human iPSC models using CRISPR have been created, including triple MAPT mutation lines (Szabo et al., 2023; García-León et al., 2018; D'Brant et al., 2024 preprint).

With regard to primary cell lines, patient-derived primary fibroblasts carrying the N279K mutation are available for request from the Coriell repository (Wray et al., 2012).

Lastly, to facilitate recombinant protein studies, a plasmids library has been developed containing N279K mutant full-length and K18 fragment (i.e., the four-repeat microtubule-binding region) tau, including cysteine-modified variants (Karikari et al., 2020).

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References

News Citations

1. Tipping the Balance Toward Four-Repeat Tau Exacerbates Toxicity in Mice 29 Jul 2016
2. Cornucopia: LOADs of New Mouse Models Available 5 Nov 2022

Research Models Citations

1. MAPT(H1.0*N279K)-GR

Paper Citations

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