Mutational Analysis of Tau in
Chromosome 17-Linked
Dementia

Kirk Wilhelmsen, M.D., Ph.D.
University of California, San Francisco

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Clinical Syndrome

Disinhibition first sign (onset age 27-56)
usually manifested predominantly
by personality change

Dementia with relative preservation
of language and praxis

Parkinsonism without tremor or
response to L-DOPA progressing to
akinetic mutism

Amyotrophy which is frequently
subtle

Complex, with all of the above
features present to varying degrees

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Eponyms for FTDP-17

Disinhibition dementia parkinsonism
amyotrophy complex

Pallido-ponto-nigral degeneration

Hereditary dysphasic dementia

Atypical Pick's

Frontotemporal dementia

Primary progressive aphasia

Familial progressive subcortical gliosis

Presenile dementia with psychosis

Familial multisystem tauopathy with presenile
dementia

Pick's disease complex

Dementia lacking distinguishing features

Autosomal dominant dementia with
widespread neurofibrillary tangles

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Clinical and Pathological Heterogeneity

The clinical pattern of disease reflects the
topologic patterns of neuronal loss and gliosis.

There are family specific patterns of disease:
right vs. left
rostral vs. caudal
degree of subcortical involvement

Variable inheritance

Extrapyramidal and pyramidal involvement

Varied tau pathology

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Survey for tau mutations

140 subjects with nonAD dementia--
(principally FTD, PSP, and CBDG) were
screened for known mutations.

Very few cases were found to have known
mutations.

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Genetic evidence for the
involvement of Tau in
progressive supranuclear palsy

C Conrad, A Andreadis, JQ

Trojanowski, DW Dickson, D

Kang, X, Chen, W Wiederholt, L

Hansen, E Masliah, LJ Thal, R

Katzman, Y Xia, T Saitoh

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Are there founder effects
among FTD cases?

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Search For Linkage
Disequilibrium in FTD

20 unrelated cases and 20 controls from
Lund were genotyped for 20 markers in
the region containing D17S791-D17S800

A high resolution radiation hybrid map
was constructed

Three marker haplotypes were identified
with an estimated frequency of 18% in
controls and 63% in affecteds ([delta]~0.5)

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Screening the tau gene for
mutations

140 subjects sequenced:
90 FTD (-11 samples from 4 families),
40 PSP,
10 Misc.

15 exons and 1 kb of promoter sequenced in
both directions from all subjects (600kb)

Denaturing HPLC done to check that no
variants missed

All variants confirmed by second method

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Results

71 sequence dimorphic variants
identified:
29 with heterozygosity > 0.10,
32 variants found in exons not normally used
in humans or untranslated regions

Three rare amino acid substitutions
were found in PSP patients (exons 1,
4, & 7)

One family with FTD with evidence
of linkage has a new exon 10
mutation

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Results (cont.)

The PSP cases have a recurrent
genotype including both common
and rare polymorphisms

The Swedish FTD cases have a
common genotype for common
polymorphisms

Other FTD cases have recurrent
rare genotypes:
e.g. four FTD cases with exon 4A a
substitution not found in ~400
chromosomes

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Conclusions?

Most FTD and PSP cases
don't have the known
mutations

There is still something to
find in or near tau:
possibly even another gene

We need a functional test to
test candidate mutations

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Wilhelmsen Lab	G Schellenberg	FTD/PSP
Toby Nygaard	P Poorkaj	A Brun
Amy Pavlou	T Bird	L Gustafson
Mat Bernstein	D Geschwind	B Miller
Tim Lynch	D Li	J Cummings
Lorraine Clark	PPND	W Jagust
Columbia Clinical Group	Z Wszolek	D Mungus
Karen Bell	F Arwert	J Mastrianni
Karen Marder	DDPAC	L Reed
Lewis Rowland	N Foster	J Trojanowski
Stan Fahn	Pet/Spect	V M-Y Lee
Richard Mayeux	S Minoshima
Pathology	I Prohovnik
Anders Sima	FPSG
Richard Defendini	D Lanska
Cathy Keohane	P Gambetti

We thank our patients and NINDS
(KCW supported by NS31212-04 & NS36733-01)