Unknown, but brain imaging indicates heterogeneity, including frontal and temporal lobe atrophy, cerebral vascular lesions, and lateral ventricle enlargement. In one case, CSF biomarkers consistent with AD were reported.

Unknown. In silico predictions were mixed; PHRED-scaled CADD was below the threshold for deleteriousness (15.48).

Unknown.

In vitro, this mutation affects exon 10 splicing, resulting in the overproduction of tau isoforms containing four microtubule binding repeat domains (4R tau).

PSP neuropathology, including 4R-tau aggregation, phosphorylated tau-immunoreactive coiled bodies, and tufted astrocytes. Also, CBD neuropathology.

Mixed results; possibly enhances MAPT transcription.

Not applicable.

Unknown; predicted probably damaging in silico.

Unknown, but MRI of two carriers showed frontal atrophy, with one also having temporal atrophy and the other microangiopathy. FDG-PET showed hypoperfusion in frontal and temporal lobes of one carrier.

Unknown, but PHRED-scaled CADD score (20.4) predicted a damaging effect.

In one case, neuronal loss in the frontal and temporal lobes; tau deposits predominantly in glia, progressive supranuclear palsy-like straight tubules; accumulation of 4-repeat (4R), Sarkosyl-insoluble tau.

Promoted fibril formation in vitro, but not in a cell-based assay. Reduced microtubule assembly in vitro; increased microtubule binding in cells.

Aggregated insoluble tau in subcortical regions was predominantly 4-repeat (4R) tau with 0 or 1 amino terminal inserts (i.e. 0N4R or 1N4R). Insoluble tau in cortical regions also contained 1N3R tau.

Mixed results regarding effects on microtubule dynamics and tau aggregation. Multiple cellular processes affected in a Drosophila model.

Not applicable.

Unknown.

Not applicable.

In silico analysis predicted a possible effect on protein function.

Not applicable.

Unknown.

Not applicable.

Unknown.

Unknown.

Unknown.

Unknown.

Unknown.

Unknown; frontal and temporal atrophy by MRI.

In vitro 4-repeat (4R) tau with the G55R mutation nucleates microtubule assembly more effectively than wild-type 4R tau. This effect appears to be isoform-specific, and was not seen in 3R tau.

Frontotemporal atrophy and fronto-mesial and parietal left hypoperfusion.

Unknown, but in silico algorithm did not reach deleteriousness threshold (PHRED-scaled CADD = 13.34).

Frontal hypometabolism by PET.

No effect on normal splicing of exons 2 or 3; Creation of a predicted phosphorylation site and a predicted O-glycosylation site.

Unknown.

Unknown; predicted benign in silico.

Not applicable.

Unknown; predicted possibly damaging in silico.

Not applicable.

Unknown.

Not applicable.

Unknown.

Unknown.

Unknown; predicted possibly damaging in silico.

Unknown.

Unknown; predicted possibly damaging in silico.

Not applicable.

Unknown.

Unknown.

Unknown.

Not applicable.

Unknown.

Not applicable.

Unknown.

Unknown.

Unknown.

Not applicable.

Unknown.

Not applicable.

Unknown; predicted probably damaging in silico.

Unknown.

Unknown; predicted to be probably damaging in silico.

Not applicable.

Unknown.

Not applicable.

Unknown.

Unknown.

Unknown.

Extremely variable: Typically prominent tau pathology with variable involvement of Lewy bodies, amyloid plaques, or TDP-43 pathology.

Reduced ability to bind microtubules; Less efficient microtubule assembly and impaired microtubule stability; More prone to tau oligomer formation and proteolysis by caspases.

Not applicable.

Unknown.

Not applicable.

Unknown.

Not applicable.

Unknown.

Not applicable.

Unknown.

Not applicable.

Unknown; predicted probably damaging in silico.

Unknown.

Unknown.

Not applicable.

Unknown. This variant segregates with the H2 haplotype, which may be associated with decreased tau levels in the brain.

Found in an individual with tau-negative microvacuolar-type neuropathology attributed to a GRN mutation.

Unknown.

Widespread atrophy, particularly severe in the temporal and frontal lobes, the caudate nucleus, the hippocampus, and the amygdala. Neurofibrillary tangles, pretangles, neuropil threads, and Pick bodies; neuronal inclusions composed of 3R-tau, while astrocytic inclusions contained 4R-tau.

Unknown.

Not applicable.

Unknown.

Frontotemporal atrophy, especially in the temporal lobes. Tau+ Pick bodies in the neocortex, hippocampus, and some subcortical regions. Diffuse hyperphosphorylated tau in some cell bodies. Balloon neurons, ramified astrocytes, threads, coiled bodies, and globular oligodendroglial inclusions in the gray and white matter.

Reduces ability to promote microtubule assembly; decreases cathepsin cleavage resulting in reduced lysosomal degradation. Reduced LRP1 binding.

Extensive tau pathology, but no neurofibrillary tangles or Pick bodies. Mild macroscopic atrophy of the frontal lobes and dilatation of the anterior lateral ventricles, bilateral subdural hematomas. Neurodegeneration with gliosis, mild microvacuolation, and neuronal atrophy and loss in the frontal lobes.

Selective increase in tau aggregation (four-repeat isoforms only); No disruption of exon 10 splicing.

Severe atrophy of the frontal and temporal lobes; Extensive neuronal loss and gliosis; Many tau-positive inclusions, including Pick bodies; Tau-positive argyrophilic astrocytes with stout filaments and round or irregular argyrophilic inclusions.

Increased levels of exon 10+ tau mRNA and soluble four-repeat (4R) tau; Decreased rate and extent of tau-induced microtubule assembly; A 3R isoform-specific increase in tau self-assembly.

Not applicable.

Unknown.

Not applicable.

Unknown.

Severe frontotemporal lobe atrophy; Neuronal loss in hippocampus and caudate nucleus; "Ballooned cells" in cortex and basal ganglia; Tau-positive inclusions in multiple cortical and subcortical areas.

Mutant tau proteins are more favorable substrates for phosphorylation than wild-type tau.

Unknown.

Unknown.

Severe frontotemporal atrophy with relative sparing of the motor and visual cortices. Severe hippocampal pathology with neurons replaced by a dense band of astrocytic gliosis. Abundant tau pathology, primarily consisting of 3-repeat (3R) tau isoforms, consistent with Pick's disease. Ghost tangles in the cortex.

When co-transfected with another splice-site variant, this mutation decreases the inclusion of exon 10, generating more E10^- transcripts and resulting in an overproduction of 3-repeat (3R) tau isoforms.

Four-repeat (4R) tauopathy with neuronal and glial tau inclusions.

This intronic mutation stregthens the splice acceptor site, resulting in more frequent inclusion of exon 10 into mRNA transcripts.

Neuronal loss, gliosis, and accumulation of 4R tau in multiple brain areas including the temporal lobe, amygdala, and substantia nigra.

Alters the splice site resulting in more frequent inclusion of exon 10 into mRNA transcripts.

Widespread neuronal and glial tau accumulation in the cortex, basal ganglia, brain-stem nuclei, and white matter. Insoluble fraction is primarily 4R tau. Prominent tau deposition in the medial temporal cortices and upper and lower motor neurons with corticospinal tract degeneration.

Affects splicing similar to many of the intronic mutations, resulting in more frequent inclusion of exon 10 in mRNA transcripts. Also, reduces lysosomal degradation of tau in iPSC-derived neurons.

Variable: Pick bodies comprised of 3R but not 4R tau and severe atrophy of the frontal and temporal cortices. Alternatively, tangles (Braak stage IV), neuritic amyloid plaques, extensive Lewy body pathology, moderate to severe atherosclerosis in brain vessles, and mild amyloid angiopathy.

The K280del variant is unusal in that it inhibits exon 10 inclusion and leads to an excess of 3-repeat (3R) tau transcripts. It also has been shown to reduce tau's ability to promote microtubule assembly.

Unknown.

Unknown.

A variety of tau aggregates in both neurons and glia. In addition, a substantial number of diffuse and neuritic Aβ plaques, possibly due to coincident AD.

The silent L284L increases transcripts containing exon 10 and decreases transcripts lacking exon 10. The mutation is thought to destroy an exon-splicing silencing element.

Unknown.

Unknown.

Unknown; MRI showed global atrophy of the cerebrum, especially in the left posterior frontal lobe.

Unknown. In silico analysis predicted an increase in exon 10 splicing.

Localized frontotemporal lobe atrophy; A proliferation of tau-positive astrocytes; An accumulation of phosphorylated tau in both neurons and glia; An accumulation of four-repeat (4R) tau.

This mutation increases the inclusion of exon 10 in tau mRNA and therefore increases the ratio of 4R/3R tau. It reduces tau's ability to promote tubulin polymerization and microtubule assembly. It has little to no effect on tau filament formation.

Unknown; imaging showed temporal atrophy.

Unknown.

Atrophy of the right precentral gyrus and the brainstem, as well as neuron loss and gliosis in the substantia nigra, several brainstem nuclei, and diencephalon. Hyperphosphorylated tau and neurofibrillary tangles in neurons in many brain regions. Accumulated tau in astrocytes and oligodendrocytes.

The N296del mutation has little or no effect on exon 10 splicing, but substantially reduces tau's ability to promote microtubule assembly and increases its aggregation into filaments.

Frontotemporal atrophy; Neuronal loss in the globus pallidus, substantia nigra, and locus ceruleus; Swollen achromatic neurons and tau-positive inclusions throughout the brain; Plaques and tangles were rare in the hippocampus and cerebral cortex.

Increased inclusion of exon 10 in tau mRNA and thus increased the ratio of 4R/3R tau protein.

Unknown.

Unknown.

Not applicable.

Unknown; predicted benign and well-tolerated in silico.

Globular deposits composed of four-repeat tau in astrocytes and oligodendrocytes, characteristic of globular glial tauopathy. Neuron loss in frontal cortex, substantia nigra, and spinal cord; spongiosis and astrogliosis in cortex and subcortical regions; neurofibrillary tangles; and demyelination of the corticospinal tracts.

Unknown.

Heterogenous. Frontotemporal atrophy and extensive inclusions of hyperphosphorylated tau in neurons and glia. Subcortical regions also affected.

Enhances tau's ability to aggregate and seeding potency. Reduces tau's ability to promote microtubule assembly and bind to microtubules, with increased binding of tubulin dimers. Reduces binding to protein phosphatase 2A.

Tau aggregates consisting mainly of 4-repeat (4R) isoforms. Numerous intracytoplasmic tau deposits in neurons and glia in multiple brain regions, including the hippocampus, neocortex, and substantia nigra. Severe neuronal loss, gliosis, and a few ballooned cells in the frontal and temporal cortices.

Strongly promotes β-sheet formation in 4R tau and accelerates the formation of paired helical filament. Decreases tau's ability to promote microtubule assembly.

Patient had severe neuronal loss in the frontal and temporal cortices, globus pallidus, substantia nigra, red nucleus, and dentate nucleus. Tau-positive fibrillar structures in neurons and glia in these regions. The pathology was attributed to the IVS10+11 mutation in MAPT, which the patient also carried.

No change in the ratio of 3-repeat (3R) to 4-repeat (4R) tau isoforms.

Mild frontal and temporal atrophy with neuronal loss, gliosis, enlarged lateral ventricles, and microvacuolation. Accumulated tau in neurons and glia, including neurofibrillary tangles. Elevated 4-repeat (4R) isoforms.

Unknown.
 

Numerous neurofibrillary tangles including some with an unusual, ring-shaped morphology around the nucleus, especially in the frontal, temporal, insular, and postcentral cortices, as well as in the dentate gyrus. Neurofibrillary tangles in neurons and glia.

Stem-loop instability leading to alterations in the ratio of 3-repeat (3R) tau to 4-repeat (4R) tau. Reduced lysosomal degradation of tau.

Extensive neuronal loss in the medial temporal cortex, hippocampus, and amygdala. No classical neurofibrillary tangles, Pick bodies, or neuritic plaques. Diffuse cytoplasmic tau in neurons, coiled bodies in oligodendrocytes, and argyrophilic grains. The tau-positive structures were composed only of 4-repeat (4R) isoforms.

Affects exon 10 splicing, causing an overproduction of 4-repeat (4R) tau isoforms.

Variable, but associated with cell loss, ballooned neurons, and tau-positive astrocytes, but limited cortical atrophy. Silver-positive neurofibrillary tangles associated with PSP diagnosis but not with FTDP-17 diagnosis.

This silent mutation increases the splicing in of exon 10 and results in overproduction of tau isoforms containing four repeats (4R).

Abundant filamentous tau deposits in the neocortex, some in subcortical nuclei, brainstem, and spinal cord. Deposits in neurons and glia, especially oligodendrocytes. Tau filaments are twisted and consist of 4-repeat (4R) tau isoforms.

Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10r, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms..

Severe frontotemporal atrophy with relative sparing of the motor and visual cortices. Severe hippocampal pathology with neurons replaced by a dense band of astrocytic gliosis. Abundant tau pathology, primarily consisting of 3-repeat (3R) tau isoforms, consistent with Pick's disease. Ghost tangles in the cortex.

When co-transfected with another splice-site variant, decreases the inclusion of exon 10, resulting in an overproduction of 3-repeat (3R) tau isoforms.

Severe neuronal loss in the frontal and temporal cortices, globus pallidus, substantia nigra, red nucleus, and dentate nucleus. Tau-positive fibrillar structures in neurons and glia.

Alters the splicing of exon 10, resulting in increased 4-repeat (4R) tau relative to 3-repeat (3R) tau.

Tau aggregates in neurons and glia; Isolated tau filaments with twisted, ribbon-like morphology comprised of hyperphosphorylated 4-repeat (4R) tau isoforms.

Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

Severe "knife‐edge" atrophy in the frontal and temporal lobes; Frequent neurofibrillary and glial tangles; Occasional ballooned neurons and damage to the substantia nigra.

Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

Atrophy and spongiform changes in the frontotemporal cortex; Neuronal loss and gliosis in the substantia nigra and amygdala; Deposition of 4R tau.

Destabilizes a stem-loop structure that regulates alternative splicing of exon 10, causing more frequent inclusion of exon 10 and leading to an increase in the proportion of four-repeat (4R) tau isoforms.

Unknown; imaging showed bilateral anterior temporal lobe atrophy and hypometabolism.

Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

Neuronal loss, gray-matter gliosis, and neuropil vacuolation in both the frontal and temporal lobes. Balloon neurons in the cortex and degeneration of the substantia nigra with free melanin. Tau-positive neurons.

Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

Frontal lobe atrophy; Frontal hypoperfusion.

Alters the splicing of exon 10, resulting in increased 3-repeat (3R) tau isoforms. Elevated 3R tau was shown to decrease microtubule assembly.

Not applicable.

Unknown.

Not applicable.

IVS10 + 29 G>A does not appear to alter the splicing of exon 10.

Extensive tau pathology in neurons (Pick-like inclusions) and astrocytes, particularly in the frontotemporal cortex and hippocampus. Tau extracted from the cerebral cortex was present in straight and twisted tau filaments.

Recombinant L315R tau protein has a compromised ability to promote microtubule assembly.

Unknown.

Unknown.

Severe degeneration of the substantia nigra with extensive neuronal loss and gliosis. No Lewy bodies or Pick’s bodies. Severe neuron loss in the motor bulbar nuclei and anterior horn of the spinal cord. Frequent, diverse inclusions in oligodendrocytes and astrocytes. Phospho-tau-positive pre-tangles and tangles in neurons.

Mutant mouse brain homogenates induced seeding and spreading of 4R and 3R tau in wildtype mouse brains.

Lobar atrophy, especially in the inferior frontal gyrus. White-matter pathology, including vacuoles, gliosis, and loss of myelinated fibers. Extensive tau pathology, with tau-positive inclusions in neurons, astrocytes and oligodendrocytes. Distribution of tau pathology consistent with globular glial tauopathy, subtype III.

Impaired tubulin polymerization. Altered tau aggregation in an isoform-specific manner; accelerated tau assembly in 4R tau while decreasing tau aggregation, misfolding, and filament assembly in 3R tau.

Neuropathology consistent with Pick's disease. Focal bilateral atrophy of the anterior temporal lobes with only very mild frontal atrophy; Severe neuronal loss and gliosis in the temporal cortex, cingulate gyrus, entorhinal cortex, and hippocampus.

A marked reduction in the ability of tau to promote microtubule assembly; Removal of a potential phosphorylation site in tau.

Atrophy of primary motor and premotor cortices; neuronal tau-positive lesions mimicking Pick bodies, especially in the dentate gyrus, and containing aggregates of both 3-repeat (3R) and 4-repeat (4R) tau proteins.

Reduced capacity to bind microtubules.

Degeneration of the frontal and temporal lobes, hippocampus, and substantia nigra. Extensive deposition of tau, neurofibrillary tangles, and neuropil threads, but no Pick bodies. Tau-positive inclusions in neurons and glia. Sarkosyl-insoluble tau showed paired helical and straight filaments, and more irregular rope-like filaments.

Reduced ability of tau to promote microtubule assemby.

Unknown.

Reduced ability of tau to promote microtubule assembly; Increased heparin-induced assembly of recombinant tau into filaments.

Neuron loss in frontal and temporal cortices and substantia nigra. Neurofibrillary tangles composed of 3R- and 4R-tau. Astrocytic inclusions composed of 4R tau.

Unknown, but other mutations at this position (G335S, G335V) reduce the ability of tau to promote microtubule assembly.

Atrophy of the frontal lobes, anterior temporal lobes, hippocampus, and amygdala. In some areas neuronal loss and astrogliosis were severe, leading to spongiosis. Hyperphosphorylated tau accumulated in swollen (Pick) cells. Intraneuronal inclusions (Pick bodies) containing both 3R and 4R tau and neurofibrillary tangle‐like structures.

Increases tau fibrillogenesis. In contrast to most MAPT missense mutations, Q336R increases, rather than decreases, mutant tau's ability to promote microtubule assembly.

Neuropathology consistent with Pick's disease. Focal cortical atrophy and Pick bodies (cytoplasmic inclusions in neurons that were primarily negative for Gallyas silver stain). Pick bodies contained primarily 3R tau. Pick cells, called “swollen achromatic neurons” or “ballooned neurons,” were frequent in some brain regions.

Increased rate and steady-state levels of microtubule polymerization; Greater tau filament assembly and aggregation, especially for 3R tau.

Neurofibrillary tangles comprised of paired helical filaments without plaques in several regions of the neocortex, amygdala, and parahippocampal gyrus.

Accelerates aggregation of tau into filaments. The mutant protein also makes a more favorable substrate for phosphorylation than wild-type 4-repeat (4R) tau. Alters axon base, interfering with neuronal plasticity and electrical homeostasis.

Prominent frontotemporal neuron loss, cytoplasmic tau aggregates, paired helical tau filaments, increased 4-repeat (4R) tau mRNA, increased 4R tau without E2 or E3 inserts (4R0N), decreased 4R tau with these inserts (4R1N and 4R2N).

Unknown.

In one case, mixed 3R/4R tau pathology with neurofibrillary tangles most prominent in medial temporal lobes. Frontotemporal cerebral atrophy, particularly severe in the anterior medial temporal lobes.

Unknown, but in silico algorithms predicted a damaging effect (PHRED-scaled CADD = 24.7).

Extensive tau neuropathology.

Recombinant S352L tau exhibited reduced microtubule binding and accelerated filament formation.

Frontotemporal and hippocampal atrophy. Some spongiosis. Abundant tau pathology (e.g., mature neurofibrillarly tangles and pretangles, tau-positive threads and grains). β-amyloid pathology largely absent.

Unknown.

Unknown.

Unknown.

Unknown; MRI showed massive brain atrophy.

Unknown.

Neuronal loss and reactive gliosis in many regions, including the nucleus basalis of Meynert, substantia nigra, locus coeruleus, motor cortex, and the anterior horn of the spinal cord. Neuronal tau inclusions, especially globose neurofibrillary tangles with some flame-shaped neurofibrillary tangles. Some Pick body-like inclusions in one case.

Reduced ability to promote microtubule assembly compared with wild-type tau and an increased rate of tau aggregation; Increased chromosomal instability and copy-number variations in lymphocytes and fibroblasts of mutation carriers.

Unknown; MRI showed moderate to severe symmetrical cerebral atrophy predominantly involving the frontal lobe with ventricular enlargement.

Reduced ability to promote microtubule assembly compared with wild-type tau, but similar aggregation kinetics; Increased chromosomal instability and copy number variations in lymphocytes and fibroblasts of mutation carriers.

Brain atrophy, especially in the temporal lobes. Numerous tau-positive Pick bodies and Pick cells indistinguishable from those of sporadic Pick's disease in the neocortex, hippocampus, and subcortical brain regions.

Recombinant tau proteins with the K369I mutation showed reduced ability to promote microtubule assembly.

Tau-positive Pick body-like neuronal inclusions and swollen, tapering, thread-like processes in white matter. Atrophy of the frontal and temporal lobes, hippocampus, and amygdala. Gliosis, neuron loss in the hippocampus and substantia nigra, and corticospinal tract degeneration.

Promotes tau filament formation and slightly decreases tau’s ability to promote microtubule assembly.

Severe frontal lobe atrophy; neuronal loss; astrocytosis; tissue vacuolation.

Recombinant G389R tau showed a reduced ability to promote microtubule assembly and an increased susceptibility to calpain I digestion.

Numerous neocortical tau-positive Pick body-like inclusions and filamentous axonal inclusions.

Recombinant G389R tau showed a reduced ability to promote microtubule assembly.

Severe atrophy of the frontal and temporal lobes, hippocampus, and amygdala. Neurofibrillary tangles, neuropil threads, Pick bodies, and astrocytic inclusions, composed of 3R-tau.

Unknown.

Unknown, but MRI revealed bilateral temporal atrophy with relative sparing of the frontal lobes in carriers.

Unknown. In silico predictions yield a range of results, but the proline-to-serine change at amino acid 397 should prevent phosphorylation of the adjacent serine 396 by proline-directed kinases.

Bilateral frontotemporal atrophy. Neuronal loss, gliosis, and abundant tau-positive inclusions, including neurofibrillary tangles. Generally sparse or absent Aβ plaques.

Reduces microtubule-binding, causes axonal degeneration and tau mislocalization to dendrites, and disrupts mitochondrial transport.

Mild atrophy of the superior frontal cortex and enlargement of the lateral ventricles. Loss of neuromelanin in the midbrain. Abundant 4R tau-positive astrocytic plaques and numerous threads in the gray and white matter. Abundant ballooned neurons in the superior frontal cortex. Significant TDP-43 pathology, especially in the basal ganglia.

Increase in the 4R/3R tau-mRNA ratio in patient brain. Recombinant tau with the N410H mutation had increased tau filament formation compared with wild-type tau, a decreased rate of microtubule assembly, and reduced overall microtubule polymerization.

Unknown; MRI showed moderate frontotemporal atrophy.

Unknown.

Neurofibrillary tangles in the hippocampus and entorhinal cortex. Aβ deposits were absent.

The genomic duplication was associated with a 60-90% increase in the mRNA levels of MAPT.

Unknown.

Unknown.