|
Mutation & Exon
|
Effect on Exon 10 splicing & Biochemistry
|
Clinical
|
Neuropathology
|
References
|
|
R5H
Posted 7/27/09
|
Decreased microtubule-promoting capacity and increased fibrillation of tau in vitro.
|
FTDP-17 of 5 years' duration in an 81-year-old man whose brother had died at age
86 years with dementia.
|
Frontal and temporal neuronal loss, glial-predominant tau deposits, progressive
supranuclear palsy-like straight tubules, accumulation of 4-repeat-predominant Sarkosyl-insoluble
tau.
|
 Hayashi
et al., 2002
|
|
R5L
Posted 7/27/09
|
Mutation alters ability of tau to promote microtubule assembly, but does not affect
the ratio of tau isoforms.
|
Progressive supranuclear palsy.
|
Aggregated insoluble tau from subcortical regions was predominantly four-repeat
tau with no or one amino terminal insert (0N4R and 1N4R). Insoluble tau from cortical
regions also contained 1N3R tau.
|
Poorkaj
et al., 2002
|
|
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
|
|
L266V
Posted 7/27/09
|
Elevated levels of exon 10+ tau RNA and soluble 4R tau. Decreased rate and extent
of tau-induced microtubule assembly, and a 3R isoform-specific increase in tau self
assembly.
|
Rapidly progressive FTD, onset at age 33 years.
|
Severe atrophy of the frontal and temporal lobes. Tau-positive Pick bodies w/ severe
neuronal loss and gliosis. RD3, a tau antibody specific for the three-repeat (3R)
isoforms, labeled the Pick bodies.
|
Hogg
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 8/13/07
|
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
|
|
L315R
Posted 7/27/09
|
Sarkosyl-insoluble tau extracted from cerebral cortex showed straight and twisted
tau filaments and a pattern of pathological tau bands similar to that of Pick's
disease. Upon dephosphorylation, only five of the six brain tau isoforms were observed,
with the shortest isoform being undetectable. Recombinant tau proteins with the
L315R mutation showed a reduced ability to promote microtubule assembly.
|
In 2 Dutch families, age at onset varied within each family, ranging from 25 to
64 years.Incomplete penetrance was established in an 82-year-old mutation carrier
with no signs of dementia and appeared probable in two additional subjects.
|
Extensive tau pathology in neurons (Pick-like inclusions) and astroglial cells,
particularly in the frontotemporal cortex and the hippocampal formation.
|
Van
Herpen et al., 2003
|
|
K317M
Posted 7/27/09
|
Two bands of 64 and 68 kDa.
|
Mean age at onset 48 y. Mean duration 6 y. Dysarthria often seen initially. Parkinsonism,
pyramidalism, half had amyotrophy. Behavioral changes not prominent. Cognitive decline
appeared late.
|
Massive degeneration of the substantia nigra without Lewy bodies. Variable degree
of frontotemporal atrophy. Corticospinal tract degeneration and anterior horn neuron
loss. Extensive deposition of abnormal tau in a mixed pattern (neuronal, glial).
|
Zarranz
et al., 2005
|
|
S320F
Posted 7/27/09
|
Recombinant tau protein with the S320F mutation showed a greatly reduced ability
to promote microtubule assembly.
|
Proband died at age 53 years, after a disease duration of 15 years.
|
Neuropathological picture similar to Pick disease.
|
Rosso
et al. 2002
|
|
Q336R
Posted 7/27/09
|
Increases tau fibrillogenesis. In contrast to most tau missense mutations, Q336R
increased, not decreased, the ability of mutant tau to promote microtubule assembly.
|
Onset at 58 years of age and disease duration of 10 years. Alterations in memory,
language, executive functions and behaviour consistent with FTD.
|
Degeneration of frontal and temporal lobes associated with presence of hyperphosphorylated
tau proteins in swollen (Pick) cells and intraneuronal inclusions (Pick bodies)
containing 3-repeat and 4-repeat tau.
|
Pickering-Brown
et al., 2004
|
|
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
|
|
S352L
Posted 7/27/09
|
N/A
|
This is the first description of a pathologically proved young-onset tauopathy with
apparent recessive inheritance. Two siblings from consanguineous marriage presented
with respiratory hypoventilation and died 10 days and 4 years later, respectively.
|
Extensive tau neuropathology.
|
Nicholl
et al., 2003
|
|
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.
|
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