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Search Results
MAPT (113)
MAPT encodes the microtubule associated protein tau, a protein central to Alzheimer’s disease neuropathology. MAPT mutations are not linked to familial forms of AD, but can cause frontotemporal dementia (FTD) and several other tauopathies. The pathogenic mutations, which can be either exonic or intronic, generally alter the relative production of tau isoforms and lead to changes in microtubule assembly and/or the propensity of tau to aggregate.
Mutation | Clinical Phenotype |
Pathogenicity | Neuropathology | Biological Effect | Genomic Position | Genomic Region | Mutation Type Codon Change |
Research Models |
Primary Papers |
---|---|---|---|---|---|---|---|---|---|
P4T |
None | AD : Benign | Not applicable. |
Unknown; predicted probably damaging in silico. |
Exon 1 | Point, Missense CCC to ACC |
0 | Sala Frigerio et al., 2015 | |
R5C |
Parkinson's Disease Dementia | PDD : Unclear Pathogenicity | Unknown. |
Unknown. |
Exon 1 | Point, Missense CGC to TGC |
0 | Schulte et al., 2015 | |
R5H |
Frontotemporal Dementia | FTD : Unclear Pathogenicity, AD : Unclear Pathogenicity | 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.
|
Reduces tau's ability to promote microtubule assembly; Increases fibril formation in vitro. |
rs63750959 |
Exon 1 | Point, Missense CGC to CAC |
0 | Hayashi et al., 2002 |
R5L |
Progressive Supranuclear Palsy | Other Tauopathy : Pathogenic | 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. |
Reduces tau's ability to promote microtubule assembly; No effect on the ratio of tau isoforms synthesized. |
rs63750959 |
Exon 1 | Point, Missense CGC to CTC |
0 | Poorkaj et al., 2002 |
H14H |
None | FTD : Benign | Not applicable. |
Unknown. |
Exon 1 | Point, Silent CAC to CAT |
0 | Guerreiro et al., 2010 | |
T17M |
None | FTD : Benign | Not applicable. |
In silico analysis predicted a possible effect on protein function. |
rs144611688 |
Exon 1 | Point, Missense ACG to ATG |
0 | Guerreiro et al., 2010 |
Y18Y |
None | FTD : Benign | Not applicable. |
Unknown. |
rs63750811 |
Exon 1 | Point, Silent TAC to TAT |
0 | Houlden et al., 1999; Guerreiro et al., 2010 |
T30A |
None | FTD : Benign | Not applicable. |
Unknown. |
Exon 1 | Point, Missense ACC to GCC |
0 | Guerreiro et al., 2010 | |
T39T |
None | FTD : Unclear Pathogenicity | Unknown. |
Unknown. |
rs63750529 |
Exon 1 | Point, Silent ACG to ACA |
0 | Houlden et al., 1999 |
A41T |
Parkinson's Disease | PD : Unclear Pathogenicity | Unknown. |
Unknown. |
rs115239819 |
Exon 1 | Point, Missense GCT to ACT |
0 | Schulte et al., 2015 |
G55R |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
Exon 2 | Point, Missense GGA to AGA |
0 | Iyer et al., 2013 | |
V75A |
Frontotemporal Dementia | FTD : Unclear Pathogenicity | Frontotemporal atrophy and fronto-mesial and parietal left hypoperfusion. |
Unknown. |
Exon 3 | Point, Missense GTG to GCG |
0 | Gallo et al., 2010 | |
G86S |
None | FTD : Unclear Pathogenicity | 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. |
rs63751135 |
Exon 3 | Point, Missense GGC to AGC |
0 | Stanford et al., 2004 |
A90V |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. |
Unknown; predicted benign in silico. |
Exon 3 | Point, Missense GCC to GTC |
0 | Sala Frigerio et al., 2015 | |
G200E |
None | FTD : Benign | Not applicable. |
Unknown; predicted possibly damaging in silico. |
rs757159453 |
Exon 4a | Point, Missense GGG to GAG |
0 | Sassi et al., 2014 |
P202L |
None | FTD : Benign | Not applicable. |
Unknown. |
rs63750417 |
Exon 4a | Point, Missense CCG to CTG |
0 | Lilius et al., 1999 |
G213R |
Alzheimer's Disease | FTD : Benign, AD : Unclear Pathogenicity | Unknown. |
Unknown; predicted possibly damaging in silico. |
rs76375268 |
Exon 4a | Point, Missense GGG to AGG |
0 | Jin et al., 2012 |
V224G |
Alzheimer's Disease, None | FTD : Benign, AD : Unclear Pathogenicity | Unknown. |
Unknown; predicted possibly damaging in silico. |
rs141120474 |
Exon 4a | Point, Missense GTC to GGC |
0 | Jin et al., 2012 |
Q230R |
Alzheimer's Disease, None | FTD : Benign, AD : Unclear Pathogenicity | Not applicable. |
Unknown. |
rs63750072 |
Exon 4a | Point, Missense CAA to CGA |
0 | Rademakers et al., 2004 |
D285N |
Progressive Supranuclear Palsy, None | FTD : Benign, Other Tauopathy : Incomplete Penetrance | Unknown. |
Unknown. |
rs62063786 |
Exon 4a | Point, Missense GAC to AAC |
0 | Poorkaj et al., 1998; Higgins et al., 1999 |
D285D |
None | FTD : Benign | Not applicable. |
Unknown. |
rs63750222 |
Exon 4a | Point, Silent GAC to GAT |
0 | Poorkaj et al., 1998 |
V289A |
None | FTD : Benign | Not applicable. |
Unknown. |
rs62063787 |
Exon 4a | Point, Missense GTA to GCA |
0 | Poorkaj et al., 1998 |
A297V |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. |
Unknown. |
Exon 4a | Point, Missense GCC to GTC |
0 | Jin et al., 2012 | |
S318L |
Alzheimer's Disease, None | AD : Unclear Pathogenicity | Unknown. |
Unknown. |
rs73314997 |
Exon 4a | Point, Missense TCG to TTG |
0 | Jin et al., 2012 |
R370W |
None | FTD : Benign | Not applicable. |
Unknown. |
rs17651549 |
Exon 4a | Point, Missense CGG to TGG |
0 | Lilius et al., 1999 |
L410F |
Alzheimer's Disease | AD : Benign | Not applicable. |
Unknown; predicted probably damaging in silico. |
Exon 6 | Point, Missense CTT to TTT |
0 | Piccoli et al., 2016 | |
S427F |
Alzheimer's Disease, None, Parkinson's Disease Dementia | PDD : Unclear Pathogenicity, AD : Unclear Pathogenicity | Unknown. |
Unknown; predicted to be probably damaging in silico. |
rs143956882 |
Exon 6 | Point, Missense TCC to TTC |
0 | Schulte et al., 2015 |
Y441H (H441Y, H47Y, His47Tyr) |
None | FTD : Benign | Not applicable. |
Unknown. |
rs2258689 |
Exon 6 | Point, Missense CAC to TAC |
0 | Poorkaj et al., 1998 |
S447P (Ser53Pro, S53P) |
None | FTD : Benign | Not applicable. |
Unknown. |
rs10445337 |
Exon 6 | Point, Missense TCC to CCC |
0 | Poorkaj et al., 1998 |
R448Ter |
Parkinson's Disease | PD : Unclear Pathogenicity | Unknown. |
Unknown. |
rs200099007 |
Exon 6 | Point, Nonsense CGA to TGA |
0 | Schulte et al., 2015 |
A152T |
Alzheimer's Disease, Corticobasal Degeneration, Dementia with Lewy Bodies, Frontotemporal Dementia, Progressive Supranuclear Palsy, pallido-nigro-luysial atrophy variant of progressive supranuclear palsy, Other Tauopathy, Parkinson's Disease Dementia | AD : Risk Modifier, FTD : Risk Modifier, DLB : Risk Modifier | 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. |
rs143624519 |
Exon 7 | Point, Missense GCC to ACC |
3 | Kovacs et al., 2010; Coppola et al., 2012 |
P176P |
None | FTD : Benign | Not applicable. |
Unknown. |
rs1052551 |
Exon 7 | Point, Silent CCG to CCA |
0 | Rizzu et al., 1999 |
A178T |
None | FTD : Benign | Not applicable. |
Unknown. |
rs63750612 |
Exon 7 | Point, Missense GCT to ACT |
0 | Houlden et al., 1999 |
T504T |
None | FTD : Benign | Not applicable. |
Unknown. |
rs62063845 |
Exon 8 | Point, Silent ACT to ACC |
0 | Higgins et al., 1999 |
P511R |
None | FTD : Benign | Not applicable. |
Unknown. |
rs768343783 |
Exon 8 | Point, Missense CCA to CGA |
0 | Schulte et al., 2015 |
P512H |
Alzheimer's Disease | AD : Benign | Not applicable. |
Unknown; predicted probably damaging in silico. |
rs192236920 |
Exon 8 | Point, Missense CCC to CAC |
0 | Piccoli et al., 2016 |
P200P |
None | FTD : Benign | Not applicable. |
Unknown. |
Exon 9 | Point, Silent CCC to CCT |
0 | Guerreiro et al., 2010 | |
R211H |
None | FTD : Benign | Unknown. |
Unknown. |
Exon 9 | Point, Missense CGC to CAC |
0 | Schulte et al., 2015 | |
A227A |
None | FTD : Benign | Not applicable. |
Unknown. This variant segregates with the H2 haplotype, which may be associated with decreased tau levels in the brain. |
rs1052553 |
Exon 9 | Point, Silent GCA to GCG |
0 | Rizzu et al., 1999 |
A239T |
Frontotemporal Dementia | FTD : Benign | Found in an individual with tau-negative microvacuolar-type neuropathology attributed to a GRN mutation. |
Unknown. |
rs63750096 |
Exon 9 | Point, Missense GCC to ACC |
0 | Pickering-Brown et al., 2002 |
D252V |
Frontotemporal Dementia | FTD : Unclear Pathogenicity | 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. |
Exon 9 | Point, Missense GAC to GTC |
0 | Shafei et al., 2020 | |
N255N |
None | FTD : Benign | Not applicable. |
Unknown. |
rs17652121 |
Exon 9 | Point, Silent AAT to AAC |
0 | Poorkaj et al., 1998 |
K257T |
Tauopathy consistent with Pick's Disease | Other Tauopathy : Pathogenic, FTD : Unclear Pathogenicity | Frontotemporal atrophy, especially in the temporal lobes. Numerous tau-positive Pick bodies in the neocortex, hippocampus, and some subcortical regions, which resembled those of sporadic Pick's disease. Diffuse hyperphosphorylated tau in some cell bodies. |
Impairs its own lysosomal degradation; reduces ability to promote microtubule assembly. |
rs63750129 |
Exon 9 | Point, Missense AAG to ACG |
0 | Rizzini et al., 2000; Pickering-Brown et al., 2000 |
I260V |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63751249 |
Exon 9 | Point, Missense ATC to GTC |
0 | Grover et al., 2003 |
L266V |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750349 |
Exon 9 | Point, Missense CTG to GTG |
1 | Kobayashi et al., 2003; Hogg et al., 2003 |
L266L |
None | FTD : Benign | Not applicable. |
Unknown. |
Exon 9 | Point, Silent CTG to CTA |
0 | Guerreiro et al., 2010 | |
P270P |
None | FTD : Benign | Not applicable. |
Unknown. |
rs11568305 |
Exon 9 | Point, Silent CCG to CCA |
0 | Rizzu et al., 1999 |
G272V |
Frontotemporal Dementia, Tauopathy consistent with Pick's Disease | FTD : Pathogenic | 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. |
rs63750376 |
Exon 9 | Point, Missense GGC to GTC |
2 | Hutton et al., 1998 |
G273R |
Frontotemporal Dementia | FTD : Pathogenic | Unknown. |
Unknown. |
Exon 9 | Point, Missense GGG to AGG |
0 | van der Zee et al., 2006 | |
IVS9-15 T>C |
Frontotemporal Dementia | FTD : Unclear Pathogenicity | 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. |
Intron 9 | Point T to C |
0 | Anfossi et al., 2011 | |
IVS9-10 G>T (g(-10)t, c.823-10G>T) |
Frontotemporal Dementia, FTD-Parkinsonism | FTD : Pathogenic | 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. |
rs63749974 |
Intron 9 | Point |
0 | Malkani et al., 2006; Olszewska et al., 2021 |
IVS9-7A>T (c.937-7A>T, c.823-7A>T) |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
Intron 9 | 0 | Mori et al., 2023 | ||
N279K |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750756 |
Exon 10 | Point, Missense AAT to AAG |
1 | Wszolek et al., 1992 |
K280del |
Alzheimer's Disease, Frontotemporal Dementia, None, Tauopathy consistent with Pick's Disease | FTD : Unclear Pathogenicity, AD : Unclear Pathogenicity | 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. |
rs63750688 |
Exon 10 | Deletion AAG to --- |
2 | Momeni et al., 2009; Rizzu et al., 1999 |
L284R |
Progressive Supranuclear Palsy | Other Tauopathy : Pathogenic, FTD : Benign | Unknown. |
Unknown. |
Exon 10 | Point, Missense CTT to CGT |
0 | Rohrer et al., 2011 | |
L284L |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63751423 |
Exon 10 | Point, Silent CTT to CTC |
0 | D'Souza et al., 1999 |
S285R |
Progressive Supranuclear Palsy | FTD : Unclear Pathogenicity, PSP : Pathogenic | Unknown. |
In vitro, this mutation affects exon 10 splicing, resulting in the overproduction of tau isoforms containing four microtubule binding repeat domains (4R tau). |
Exon 10 | Point, Missense AGC to CGC |
0 | Ogaki et al., 2012 | |
V287I |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. |
Unknown. |
rs149280278 |
Exon 10 | Point, Missense GTC to ATC |
0 | Jin et al., 2012 |
C291R |
Apraxia of Speech, Corticobasal Syndrome | Corticobasal Syndrome : Unclear Pathogenicity | 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. |
Exon 10 | Point, Missense TGT to CGT |
0 | Marshall et al., 2015 | |
N296del |
Progressive Supranuclear Palsy, Parkinson's Disease | Other Tauopathy : Pathogenic | 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. |
rs63751392 |
Exon 10 | Deletion AAT to --- |
0 | Pastor et al., 2001 |
N296H |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750416 |
Exon 10 | Point, Missense AAT to CAT |
0 | Iseki et al., 2001 |
N296D |
Frontotemporal Dementia | FTD : Pathogenic | Unknown; imaging showed temporal atrophy. |
Unknown. |
Exon 10 | Point, Missense AAT to GAT |
0 | Cohn-Hokke et al., 2014 | |
N296N |
Frontotemporal Dementia, Progressive Supranuclear Palsy | FTD : Pathogenic, PSP : Pathogenic | 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. |
rs63750912 |
Exon 10 | Point, Silent AAT to AAC |
0 | Spillantini et al., 2000 |
V300I |
None | FTD : Benign | Not applicable. |
Unknown; predicted benign and well-tolerated in silico. |
Exon 10 | Point, Missense GTC to ATC |
0 | Guerreiro et al., 2010 | |
P301S |
Frontotemporal Dementia | FTD : Pathogenic | Frontotemporal atrophy and extensive inclusions of hyperphosphorylated tau in neurons and glia. |
Recombinant tau protein with the P301S mutation showed a greatly impaired ability to promote microtubule assembly. |
rs63751438 |
Exon 10 | Point, Missense CCG to TCG |
6 | Bugiani et al., 1999; Sperfeld et al., 1999; Lossos et al., 2003 |
P301T |
Corticobasal Syndrome, Frontotemporal Dementia, Globular Glial Tauopathy | FTD : Pathogenic, CBS : Pathogenic, GGT : Pathogenic | 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. |
rs63751438 |
Exon 10 | Point, Missense CCG to ACG |
0 | Lladó et al., 2007; Erro et al., 2019 |
P301L |
Frontotemporal Dementia | FTD : Pathogenic | 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 and accelerates the formation of paired helical filament; Does not affect exon 10 splicing. |
rs63751273 |
Exon 10 | Point, Missense CCG to CTG |
10 | Hutton et al., 1998; Dumanchin et al., 1998; Clark et al., 1998; Spillantini et al., 1998 |
P301P |
Frontotemporal Dementia | FTD : Benign | 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. |
rs63751395 |
Exon 10 | Point, Silent CCG to CCA |
0 | Miyamoto et al., 2001 |
G303V |
Progressive Supranuclear Palsy | Other Tauopathy : Pathogenic, FTD : Benign | 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. |
rs63751391 |
Exon 10 | Point, Missense GGC to GTC |
0 | Ros et al., 2005 |
S305N |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63751165 |
Exon 10 | Point, Missense AGT to AAT |
0 | Iijima et al., 1999; Kobayashi et al., 2002 |
S305I |
Argyrophilic Grain Disease | FTD : Benign, Other Tauopathy : Unclear Pathogenicity | 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. |
Exon 10 | Point, Missense AGT to ATT |
0 | Kovacs et al., 2008 | |
S305S |
Frontotemporal Dementia, Progressive Supranuclear Palsy | FTD : Pathogenic, Other Tauopathy : Pathogenic | 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). |
rs63750568 |
Exon 10 | Point, Silent AGT to AGC |
0 | Stanford et al., 2000; Skoglund et al., 2008 |
IVS10+3 G>A |
Frontotemporal Dementia | FTD : Pathogenic | 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.. |
rs63750013 |
Intron 10 | Point G to A |
0 | Spillantini et al., 1998 |
IVS10+4 A>C |
Frontotemporal Dementia | FTD : Unclear Pathogenicity | 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. |
Intron 10 | Point A to C |
0 | Anfossi et al., 2011 | |
IVS10+11 T>C |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63751394 |
Intron 10 | Point, Missense T to C |
0 | Kowalska et al., 2002; Miyamoto et al., 2001 |
IVS10+12 C>T |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750916 |
Intron 10 | Point C to T |
0 | Yasuda et al., 2000 |
IVS10+13 A>G |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750308 |
Intron 10 | Point A to G |
0 | Hutton et al., 1998 |
IVS10+14 C>T |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750972 |
Intron 10 | Point C to T |
0 | Hutton et al., 1998 |
IVS10+15 A>C |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
Intron 10 | Point A to C |
0 | McCarthy et al., 2015 | |
IVS10+16 C>T |
Alzheimer's Disease, Frontotemporal Dementia, Progressive Supranuclear Palsy | FTD : Pathogenic | 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. |
rs63751011 |
Intron 10 | Point C to T |
2 | Hutton et al., 1998 |
IVS10+19 C>G |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750162 |
Intron 10 | Point C to G |
0 | Stanford et al., 2003 |
IVS10+25 C>T |
None | FTD : Benign, AD : Benign | Not applicable. |
Unknown. |
rs63750117 |
Intron 10 | Point C to T |
0 | Roks et al., 1999 |
IVS10+29 G>A |
None | FTD : Benign | Not applicable. |
IVS10 + 29 G>A does not appear to alter the splicing of exon 10. |
rs63751443 |
Intron 10 | Point G to A |
0 | D'Souza et al., 1999; Roks et al., 1999 |
L315R |
Frontotemporal Dementia, None | FTD : Incomplete Penetrance | 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. |
rs63749855 |
Exon 11 | Point, Missense CTG to CGG |
0 | van Herpen et al., 2003 |
L315L |
Frontotemporal Dementia | FTD : Pathogenic | Unknown. |
Unknown. |
rs63751231 |
Exon 11 | Point, Silent CTG to CTA |
0 | |
K317M |
Tauopathy with Parkinsonism and Motor Neuron Disease | Other Tauopathy : Pathogenic | 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. |
rs63750092 |
Exon 11 | Point, Missense AAG to ATG |
0 | Zarranz et al., 2005 |
K317N |
Globular Glial Tauopathy | GGT : Pathogenic | 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. |
Exon 11 | Point, Missense AAG to AAC |
0 | Tacik et al., 2015 | |
S320F |
Frontotemporal Dementia, Tauopathy consistent with Pick's Disease | FTD : Pathogenic | 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. |
rs63750635 |
Exon 11 | Point, Missense TCC to TTC |
0 | Rosso et al., 2002 |
P332S |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
Exon 11 | Point, Missense CCA to TCA |
0 | Deramecourt et al., 2012 | |
G335S |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750095 |
Exon 12 | Point, Missense GGC to AGC |
0 | Spina et al., 2007 |
G335A |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
Exon 12 | Point, Missense GGC to GCC |
0 | Ando et al., 2020 | |
G335V |
Frontotemporal Dementia | FTD : Pathogenic | Unknown. |
Reduced ability of tau to promote microtubule assembly; Increased heparin-induced assembly of recombinant tau into filaments. |
rs63750905 |
Exon 12 | Point, Missense GGC to GTC |
0 | Neumann et al., 2005 |
Q336R |
Frontotemporal Dementia, Pick's disease | FTD : Pathogenic | 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. |
rs63750573 |
Exon 12 | Point, Missense CAG to CGG |
0 | Pickering-Brown et al., 2004 |
Q336H |
Pick's disease | FTD : Pathogenic, Pick's disease : Pathogenic | 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.
|
Exon 12 | Point, Missense CAG to CAC |
0 | Tacik et al., 2015 | |
V337M |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750570 |
Exon 12 | Point, Missense GTG to ATG |
3 | Poorkaj et al., 1998; Sumi et al., 1992 |
E342V |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750711 |
Exon 12 | Point, Missense GAG to GTG |
0 | Lippa et al., 2000 |
S352L |
Other Tauopathy | Other Tauopathy : Pathogenic | Extensive tau neuropathology. |
Recombinant S352L tau exhibited reduced microtubule binding and accelerated filament formation. |
rs63750425 |
Exon 12 | Point, Missense TCG to TTG |
0 | Nicholl et al., 2003 |
S356T |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
Exon 12 | Point, Missense TCC to ACC |
0 | Momeni et al., 2010 | |
I360V |
Parkinson's Disease | PD : Unclear Pathogenicity | Unknown. |
Unknown. |
rs756903040 |
Exon 12 | Point, Missense ATC to GTC |
0 | Schulte et al., 2015 |
V363I |
Frontotemporal Dementia | FTD : Incomplete Penetrance | Unknown; MRI showed massive brain atrophy. |
Unknown. |
rs63750869 |
Exon 12 | Point, Missense GTC to ATC |
0 | Munoz et al., 2007; Anfossi et al., 2011 |
P364S |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
Exon 12 | Point, Missense CCT to TCT |
0 | Rossi et al., 2012 | |
G366R |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
Exon 12 | Point, Missense GGA to AGA |
0 | Rossi et al., 2012 | |
K369I |
Frontotemporal Dementia, Tauopathy consistent with Pick's Disease | FTD : Pathogenic | 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. |
rs63751264 |
Exon 12 | Point, Missense AAA to ATA |
0 | Neumann et al., 2001 |
E372G |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
Exon 13 | Point, Missense GAA to GGA |
0 | Tacik et al., 2016 | |
G389R (G>A) |
Frontotemporal Dementia, Pick's disease | FTD : Pathogenic, Other Tauopathy : Pathogenic | 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. |
rs63750512 |
Exon 13 | Point, Missense GGG to AGG |
0 | Pickering-Brown et al., 2000 |
G389R (G>C) |
Frontotemporal Dementia | FTD : Pathogenic | Numerous neocortical tau-positive Pick body-like inclusions and filamentous axonal inclusions.
|
Recombinant G389R tau showed a reduced ability to promote microtubule assembly. |
rs63750512 |
Exon 13 | Point, Missense GGG to CGG |
0 | Murrell et al., 1999; Ghetti et al., 2000; Rossi et al., 2008 |
G389_I392del |
Frontotemporal Dementia | FTD : Unclear Pathogenicity | 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. |
Exon 13 | Deletion GGG.GCG.GAG.ATC.GTG to GTG |
0 | Shafei et al., 2020 | |
P397S |
Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs1295855402 |
Exon 13 | Point, Missense CCA to TCA |
0 | Borrego-Écija et al., 2019 |
R406W |
Alzheimer's Disease, Frontotemporal Dementia | FTD : Pathogenic | 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. |
rs63750424 |
Exon 13 | Point, Missense CGG to TGG |
5 | Hutton et al., 1998 |
N410H |
Corticobasal Degeneration | Other Tauopathy : Pathogenic | 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. |
Exon 13 | Point, Missense AAT to CAT |
0 | Kouri et al., 2014 | |
T427M |
Frontotemporal Dementia, Parkinson's Disease | FTD : Pathogenic, PD : Unclear Pathogenicity | Unknown; MRI showed moderate frontotemporal atrophy. |
Unknown. |
rs63750991 |
Exon 13 | Point, Missense ACG to ATG |
0 | Giaccone et al., 2005 |
Duplication 17q21.31 |
Alzheimer's Disease | Other Tauopathy : Pathogenic | 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. |
Duplicaton |
0 | Le Guennec et al., 2016 | ||
S320Y |
Tauopathy consistent with Pick's Disease | Other Tauopathy : Pathogenic | Unknown. |
Unknown. |
Exon 11 | Point, Missense |
0 |