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Abbreviations: CBD = corticobasal degeneration. DDPAC = disinhibition-dementia-parkinsonism-amyotrophy complex; FTD = frontotemporal dementia. FTDP-17 = FTD with Parkinsonism linked to chromosome 17; HFDT = hereditary frontotemporal dementia; MSTD = multiple system tauopathy dementia; ; PPND = pallidopontonigral dementia; PSP = progressive supranuclear palsy

Mutation & Exon	Effect on Exon 10 splicing & Biochemistry	Clinical	Neuropathology	References
3'Ex10+11 T to C Posted 10/1/05	Modifies alternative splicing of exon 10, no effect on MT assembly or filament formation.	FTDP-17. Age of onset 48, duration 6 years. Initial symptoms mental retardation, myoclonus, parkinsonism (age 10). Other symptoms dementia of frontal type, Mask-like face, PSP	Neuronal loss and gliosis. Globus pallidus, thalamus, substantia nigra, dentate nuc affected. And frontal and temporal lobes. No ballooned neurons	Kowalska et al., 2002 Miyamoto et al., 2001
Exon 10 +12 "Kumamoto pedigree"	Marked reduction in melting temperature of the tau exon 10-splicing regulatory element RNA	FTD	Behaves like the 5' splice site mutations, with increments of 4R tau. Tau aggregates in degenerating neurons and glia. Twisted ribbon morphology, with hyperphosphorylated 4R tau.	Yasuda M., et al. 2000.
K257T	None. Large reduction in tau's ability to promote MT assembly. Increases ability of calpain to degrade tau (quite novel!).	n/a	Moderate atrophy of frontal areas, severe atrophy of temporal lobe. Extensive neuronal loss, florid reactive astrocytosis. Tau+ inclusions in neurons in all cortical layers. Moderate number of swollen neurons, esp. in EC.	Rizzini et al., 2000 M. Hutton, personal communication
I260V, exon 9 Updated 1/5/2004	Selective increase in tau aggregation; Decrease in tau-induced microtubule assembly with 4R tau isoforms only; I260V mutation does not disrupt exon 10 alternative splicing.	FTD with extensive tau pathology, lacks neurofibrillary tangles and Pick bodies. Age of onset of 68	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 frontal lobes. Disease is pathologically and biochemically distinct from that of the previously reported exon 9 mutations.	Grover et al., 2003
G272V exon 9	All isoforms.	HFTD2; "familial Pick's disease." Onset at 46.5; death at 54.7; duration 4-16 years. Presenting symptoms: disinhibition, incl. aggression, and/or obsessional behavior; later hyperorality, roaming, restlessness, speech loss.	Frontotemporal lobe atrophy; neuronal loss in hippocampus and caudate nucleus. "Ballooned cells"in cortex and basal ganglia. Tau+ inclusions in multiple cortical and subcortical areas; granule cells in the dentate gyrus with unique 'Pick-like' inclusions	Rizzu et al., 1999 del C Alonso et al., 2004 van Swieten et al., 1999 Barghorn et al., 2000 Rosso et al., Brain 2003 Rosso et al.abs, 2003 Goedert et al., 2000 Bronner et al., 2005 Hutton, et al.Heutink, et al. Spillantini, et al. Schenk VWD, Ann Hum Genet 1959, 23:325-333.
N279K exon 10	All isoforms, but tau+ inclusions are mainly 4-repeat. Altered RNA sequence resembles an exon splice-enhancer and leads to increased splicing of exon 10.	Pallido-ponto-nigral degeneration (PPND). Onset 43 (32-52); duration 9 (5-19); death at 52 (46-63). Present with parkinsonism or parkinsonism with personality change, progressing in 2 years to dementia and supranuclear gaze disorder.	Mild F-T atrophy. Depigmentation of substantia nigra and changes in globus pallidus and caudate. Widespread neuronal and glial fibrillary tangles, composed of ptau in twisted and straight filaments. Tau isolated from insoluble fraction is primarily 4 repeat.	Barghorn et al., 2000 Tsuboi et al., 2002 Delisle et al., 1999 Arima et al., 2000 Baba et al., 2005 Soliveri et al., 2003 Ferman et al., 2003 Jiang et al., 2003 Caviness et al., 2003 Cheshire et al., 2002 Tsuboi et al., 2002 Kowalska et al., 2001 Wszolek et al., 2000 Yasuda et al., 1999 Clark, et al. D'Souza, et al. Reed, et al.  Hasegawa, et al. Hong, et al.
ΔK280  exon 10	3-repeat tau only? Reduces splicing in exon trapping assays. Strong effect on both MT binding and tau aggregation, hence mechanism is uncertain.	Mutation seen in a single FTD patient.	n/a	Goedert et al., 2000 Rizzu et al., 1999 van Swieten et al., 1999 Barghorn et al., 2000 Rosso et al., 2003 Jiang et al., 2003 Rizzu, et al. D'Souza, et al.
L284L exon 10	Increases 4-repeat tau. Increases splicing.	"LKL pedigree." Onset 51.8±4.8; death 59-71 years. "Variant FTD", word-finding and visual- spatial difficulty; abnormal behavior.	Bilateral frontal and some temporal lobe atrophy. Amyloid as well as tau deposits.	D'Souza, et al.
ΔN296 exon 10 Posted 7/26/05	Effect mRNA and protein levels. No effect on splicing, reduced ability of tau to promote MT assembly and increased aggregation of tau into filaments.	Heterzygous individuals show PD phenotype age of onset 60-70, unknown duration. Homozygous individuals develop atypical PSP with onset (38-39) and short duration (3 yrs) with neurodegeneration.	Neuron loss and gliosis. Hyper-ptau accumulated in neurones with NFT tangles.	Ferrer et al., 2003 Yoshida et al., 2002; Grover et al., 2002; Pastor et al., 2001
N296H, exon 10, missense Posted 7/26/05	Effect on both the RNA and protein levels. Increased exon 10 splicing, reduced tau-MT assembly, no effect on tau-tau interaction.	CBD. Japanese family 3 generations. Onset age 56 and 57 with duration of 5 years.	4R tau accumulated predominantly in glial cells.	Iseki et al., 2001 Yoshida et al., 2002; Grover et al., 2002
N296N exon 10, silent mutation Posted 7/26/05	Increased splicing of exon 10. Increase in soluble 4R tau. No effect on tau-MT assembly and no effect on tau-tau interaction on filaments. WB banding 64-68.	FTDP-17 (CBD, PiD) onset 56-57, death at 69. Four individuals in three generations.	Glial and neurons.	Spillantini et al., 2000 Brown et al., 1996; Grover et al., 2002
P301L exon 10	All isoforms.	HFTD1-family. Onset 50.4; death 59; duration 4-16 years. Presenting symptoms similar to HFTD2, see G272V mutation.	Massive F-T atrophy, balloon cells, degeneration of substantia nigra; no amyloid. Tau+ inclusions: glial and neuronal tangles, irregularly twisted ribbons composed of 4R tau.	Barghorn et al., 2000 DeTure et al., 2000 van Swieten et al., 1999 Rizzu et al., 1999 Rizzu et al., 2000 Rosso et al., 2003 Rosso et al., 2000 Rosso et al., 2003 Goedert et al., 2000 del C Alonso et al., 2004 Baba et al., 2005 Sobrido et al., 2003 Walker et al., Parkinsonism Relat Disord. 2002; 9(2): 121-123 Kobayashi et al., 2002 Kowalska et al., 2001 Miyasaka et al., 2001 Poorkaj et al., 2001 Tanaka et al., 2000 Houlden et al., 1999 Nasreddine et al., 1999 Bird et al., Brain 1999; 122(Pt4); 741-756 Mirra et al., 1999 Mancuso M. et al., 2003 Hutton, et al. Heutink, et al. Spillantini, et al. 1996 Hasegawa, et al. 1998 Nacharaju, et al.
P301T Posted 13 August 2007	N/A	N/A	N/A	Lladó et al., 2007
P301S exon 10	All isoforms. Markedly reduces ability to promote microtubule assembly (similar to P301L)	"Rapidly progressing disease" in 3rd decade. Two patients in single family, one with FTD and the other with CBD.	Extensive filamentous pathology of hyperphosphorylated tau	Yasuda et al., 2002 Goedert et al., 2000 Baba et al., 2005 Lossos et al., 2003 Morris et al., 2001 Sperfeld et al., 1999 Bugiani, et al.  Goedert, et al. 1999a
G303V Exon 10 Posted 1/22/06	Effect on Exon 10 splicing and biochemistry Expression of 4 microtubule-binding repeat tau isoforms is increased in the proband.	Early-onset progressive supranuclear palsy. Onset in late 30s to early 40s.	Atrophy of mesencephalon, striatum, pons, subthalamic nuclei. Neuronal loss in substantia nigra, mild atrophy of frontotemporal cortex. NFT in glia and neurons, primarilly in mesencephalon.	Ros et al., 2005
S305N (= Ex10-2) exon 10	All isoforms.Enhanced splicing of exon 10, rather than reduced microtubule assembly.	Very early onset presenile dementia. Onset 35 (29-38); 2 patients died at 35, 41 years (3 patients described). Presenting symptoms: personality change, impaired cognition, memory loss, minimal parkinsonism.	F-T atrophy (autopsy 1 patient). Glial and neuronal; many unusual ring shaped NFT's composed of straight tubules.	Boeve et al., 2005; Kobayashi et al., 2004 Kobayashi et al., 2003 Goedert et al., 2000 D'Souza, et al. Iijima, et al. Hasegawa, et al.
+29 exon 10	No effect.	N/A	N/A	Stanford et al.
S305S Exon 10 splice site (-1)	Increased 4R tau in gray and white matter.	Onset at 48; death at 51. Presented with dystonia of left arm & dysarthria, developed supranuclear gaze palsy. Two other affected family members presented with symptoms of dementia. Onset at 36, death at 45 (one case). Frontal lobe signs, Kluver-Bucy syndrome and progressive aphasia. Skoglund et al. report a family with FTDP-17-like symptoms.	Cellular pathology characteristic of progressive supranuclear palsy. NFT's concentrated within subcortical regions of basal ganglia. Cell loss, gliosis, tufted astrocytes & ballooned neurons. Frontal and temporal atrophy, depigmented substantia nigra, gray coloration in white matter. Neocortex had marked neuronal loss, superficial spongiosis and gliosis. Many tangle- and Pick-like inclusions, mostly in small neurons in upper cortical layers. Skoglund et al. report degeneration of the frontal and temporal lobes, with extensive tau pathology in neurons and glia.	Wszolek et al., 2001 Stanford et al., Brain, 123, 880-893, 2000 Dickson, et al. Skoglund et al., 2008
V337M exon 12	All isoforms. Variable region, 4th MT repeat.	Onset 53 (42-68); death 68 (55-78); duration 12.7 years. "Presenile dementia," antisocial psychotic or belligerent behavior, relatively long disease duration.	F-T atrophy. Neuronal NFT's, "indistinguishable from AD NFTs." All six tau isoforms present in filaments	del C Alonso et al., 2004 Barghorn et al. ,2000 DeTure et al., 2000 Goedert et al., 2000 del C Alonso et al., 2004 Nacharaju et al., 1999 Spillantini, et al. Poorkaj, et al. Sumi, et al. Hasegawa, et al. 1998
E342V, exon 12, missense Posted 10/1/05	Increased exon 10 splicing, no effect on tau-tau filament formation and no effect on tau-MT assembly.	FFTDP-17 (PiD), Age of onset 49 with language and emotional difficulties. Duration 7 years.	Prominent frontotemporal neuron loss, intracytoplasmic tau aggregates, PHF, mainly 4R, location neurons	Lippa et al., 2000
K369I, missense mutation, exon 12 Posted 10/1/05	No change to exon 10 splicing. Presence of all isoforms. Reduced ability to promote microtubule assembly	FTD (PiD). Age of onset 52, rapidly progressing decline of cognitive and behavioral abilities and severe temporal atrophy. Duration 9 yr. No family history available.	Sporadic PiD because intracytoplasmic inclusions indistinguishable from Pick bodies and large numbers of Pick cells present. Increased tau filaments formation (twisted with some PHF). Insouble tau of 3R and 4R in neurons. WB banding 60, 64, 68.	Neumann et al., 2001
G389R	None. 3 and 4-repeat tau w/ large amount of 4-repeat tau w/o N-terminal inserts. Mild reduction in ability of tau to promote MT assembly. Increases ability of calpain to degrade tau (quite novel!).	Case studied by Murrell, et al. Onset at 38, duration 5 yrs, with progressive aphasia and memory disturbance, followed by apathy, indifference, and hyperphagia. Progressive rigidity, pyramidal signs and profound dementia. Case studied by Pickering-Brown, et al., onset at 32, duration 5 yrs. Obsessional and hoarding traits, decline in capabilities, becoming apathetic and largely mute. Some bilateral extrapyramidal rigidity, strong frontal grasp reflex. Diagnosis FTD.	Severe frontal lobe atrophy, milder temporal lobe atrophy. Severe neuronal loss, astrocytosis, marked tissue vacuolation. Tau+ Pick bodies and Pick cells in cortex. Many tau+ 'coiled bodies' in white matter, consistent with diagnosis of Pick's.	Gemignani et al. 2005 Ghetti et al., 2000 Goedert et al., 2000 Murrell JR, et al., and Pickering-Brown, et al., Ann Neurol. 2000 Click here for Murrell
R406W exon 13	All isoforms.	Autosomal dominant dementia with widespread NFTs. Onset 55 (45-75); generally long-lived. Insidious onset of dementia with memory loss, personality change. Some with parkinsonism and gaze disturbance.	Mild symmetric F-T atrophy; severe atrophy of hippocampus with abundant NFT's and pallor of substantia nigra with dense NFT's. Amyloid absent. Tau+ inclusions: neuronal, PHFs. Pathology meets criteria for PSP.	Saito et al., 2002 Ostojic et al., 2004 Rosso et al., 2003 Rosso et al., 2000 Barghorn et al., 2000 Perez et al., 2000 DeTure et al., 2000 van Swieten et al., 1999 Rizzu et al., 1999 Higgins et al., 1999 del C Alonso et al., 2004 Goedert et al., 2000 Hutton, et al. Reed, et al., 1997 Hasegawa, et al. 1998
3'Ex10+3, GtoA intron 3' of exon 10	4R tau; mutation enhances exon 10 splicing	Onset 49; duration 10 years. Dementia, generalized bradykinesia and rigidity, superior gaze palsy. Similarities to PS and CBD.	Diffuse atrophy of cortical, subcortical and brain stem nuclei. Neural and glial tau pathology composed of twisted ribbonlike filaments of 4R tau	Neumann et al., 2005 Tolnay et al., 2000 Spillantini, et al., 1997 Spillantini et al., 1998
3'Ex10+16 intron 3' of exon 10	4R tau; mutation enhances exon 10 splicing	Onset 53 (39-66); duration 4-15 years. FTD "Australian" pedigree (2) and others (15); PSG (10). Early personality change, loss of executive function, progressive dementia, loss of speech.	FT atrophy. Neuronal and glial tau pathology composed of wide, twisted ribbonlike filaments of 4-repeat tau	Morris et al., 2003 Janssen et al., 2002 Pickering-Brown et al., 2004 Tsuboi et al., 2003 Lantos et al., 2002 Lovestone et al., 2002 Pickering-Brown et al., 2002 Baker, et al. Goedert, et al. 1999b Hutton, et al.
3'Ex10+14 intron 3' of exon 10	4R tau; mutation enhances exon 10 splicing	Onset 45; duration 13 years. Personality change, disinhibition, progressing to withdrawn behavior and parkinsonism; amyotrophy in a few.	FT atrophy and depigmentation of substantia nigra. Ballooned neurons with tau staining.	Morris et al., 2001 Hutton, et al. Lynch, et al.
3'Ex10+13	4R tau deposited in tangles. Enhances exon 10 splicing	n/a	n/a	Hutton, et al.
3'Ex10 - 2, G to A  (aka S305N)	See S305N.	See S305N.	See S305N.	See S305N.

Other Tau-related sites:

The Tau Proteins site maintained by VCDN group of INSERM of France lists the phosphorylation sites on tau proteins and a list of mutations of the tau gene.