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Frequency of Tau Gene Mutations in Familial and Sporadic Cases of Non-Alzheimer Dementia
Parvoneh Poorkaj, PhD;
Murray Grossman, MD;
Ellen Steinbart, MA;
Haydeh Payami, PhD;
Adele Sadovnick, PhD;
David Nochlin, MD;
Takeshi Tabira, MD;
John Q. Trojanowski, MD, PhD;
Soo Borson, MD;
Douglas Galasko, MD;
Stephen Reich, MD;
Bruce Quinn, MD, PhD;
Gerard Schellenberg, PhD;
Thomas D. Bird, MD
Arch Neurol. 2001;58:383-387.
ABSTRACT
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Background Mutations in the tau gene have been reported in families with frontotemporal
dementia (FTD) linked to chromosome 17. It remains uncertain how commonly
such mutations are found in patients with FTD or non-Alzheimer dementia with
or without a positive family history.
Objective To determine the frequency of tau mutations in patients with non-Alzheimer
dementia.
Patients and Methods One hundred one patients with non-Alzheimer, nonvascular dementia, most
thought to have FTD. Of these, 57 had a positive family history of dementia.
Neuropathologic findings were available in 32. The tau gene was sequenced
for all exons including flanking intronic DNA, portions of the 3' and
5' untranslated regions, and at least 146 base pairs in the intron following
exon 10.
Results Overall, the frequency of the tau mutations was low, being 5.9% (6/101)
in the entire group. No mutations were found in the 44 sporadic cases. However,
6 (10.5%) of the 57 familial cases and 4 (33%) of the 12 familial cases with
tau pathologic findings had mutations in the tau gene. The most common mutation
was P301L.
Conclusions We conclude that tau mutations are uncommon in a neurology referral
population with non-Alzheimer dementia, even in those with a clinical diagnosis
of FTD. However, a positive family history and/or tau pathologic findings
increase the likelihood of a tau mutation. There must be other genetic and
nongenetic causes of FTD and non-Alzheimer dementia, similar to the etiologic
heterogeneity present in Alzheimer disease.
INTRODUCTION
FRONTOTEMPORAL dementia (FTD) has been increasingly recognized as a
common form of non–Alzheimer disease (AD) dementia that is clinically
characterized by behavioral problems predominating over memory loss and frontal
and temporal lobar cortical atrophy.1 A familial
subtype of FTD, often with parkinsonian features, has been linked to chromosome
17, and several mutations in the tau gene have been discovered to segregate
with the disease in most of these families.2, 3, 4, 5, 6
Because FTD and other non-AD dementias are relatively common, especially in
the presenile age group (younger than 65 years), it is important to determine
the frequency of tau mutations in this population. Thus far, only 2 studies
have addressed this issue. Rizzu et al,7 in
an FTD population from the Netherlands, found that 17.8% of cases had a tau
mutation and 43% of cases with a positive family history had a tau mutation.
Houlden et al8 studied non-AD dementia cases
from Minnesota and the United Kingdom. They found no tau mutations in 71 non-AD
cases, whereas 9.4% to 13.6% of those with pathologic findings of FTD had
tau mutations. We report herein the largest series to date from North America
of FTD and non-AD cases of dementia evaluated for mutations in the tau gene.
PATIENTS AND METHODS
We ascertained 101 unrelated index patients with non-AD, nonvascular
dementia who were thought most likely to have FTD or some variant of FTD.
The majority of these were ascertained from the Neurology and Alzheimer's
Disease Research Center clinics at the University of Washington, Seattle,
and the University of Pennsylvania, Philadelphia. Additional individual cases
were referred by several neurologists (see acknowledgments). Criteria for
inclusion were initial behavioral problems exceeding memory loss, often with
neuroimaging or neuropathologic evidence of lobar atrophy.1
Exclusion criteria were a diagnosis of typical AD, progressive supranuclear
palsy, Parkinson disease, alcoholism, vascular dementia, and Lewy body dementia.
Most of the patients had a clinical diagnosis of FTD conforming to the guidelines
of Neary et al.1 Family histories were available
for 86 cases, and those having a first-degree relative with dementia were
considered familial. Subjects with a negative family history or no available
family history were considered sporadic. These cases do not represent a random
or community-based sample but have a bias of ascertainment toward unusual
dementia referred to special academic research units. Subjects participated
through informed consent protocols approved by the relevant institutional
review boards.
Neuropathologic examination was performed on 32 brains and included
staining of microscopic sections from neocortex, hippocampus, basal ganglia,
cerebellum, and brainstem with hematoxylin-eosin, Bielschowsky silver, tau-2,
paired helical filament, and Aß-amyloid. Pathologic changes related to
tau were defined as any tau-positive cytoplasmic inclusion, which included
neurofibrillary tangles and Pick bodies.3 Eight
cases subjected to autopsy met criteria for dementia lacking distinctive histopathologic
features.9
The initial family (BK or Seattle A) with a tau mutation discovered
at the University of Washington was excluded from this study.3
DNA samples from affected persons in the families with dementia were
prepared from peripheral leukocytes as previously described.10, 11
Primer pairs for each exon from tau were used to amplify 200 ng of patient
genomic DNA in 50-µL reactions (35 cycles) containing 1X polymerase
chain reaction buffer, 200 ng of each primer, 2.5 U of Taq DNA polymerase
(Promega Corp, Madison, Wis), and 400-µmol/L deoxynucleoside triphosphatase
(Perkin-Elmer, Norwalk, Conn) (Table 1).
Polymerase chain reaction products were subjected to electrophoresis with
the use of 2.5% agarose/0.1x TAE (Tris-acetate-ethylenediaminetetraacetate)
gels and the appropriate fragments purified with a DNA purification kit (Bio
101 Inc, La Jolla, Calif). The purified fragments were sequenced automatically
with dye terminator cycle sequencing (TaqFS DNA polymerase or Big Dye Terminator
RR Mix; Perkin-Elmer), and an ABI 373 or 377 DNA Sequencer (Applied Biosystems,
Foster City, Calif).
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Table 1. Tau Exon Primers Used for Genomic PCR Amplifications and Sequencing*
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Primer pairs for amplification and sequencing tau have been described
previously.4 New primers were designed for
9 of the 11 exons to sequence deeper into the introns (Table 1) and were used for sequencing in approximately 50 of the
100 patients. Both strands of the tau gene were sequenced for all exons, including
at least 7 base pairs (bp) of flanking intronic DNA, 50 bp of the 5'-untranslated
region, and 70 bp of the 3' untranslated region. For all cases, more
than 146 bp of flanking sequence for intron 10 were analyzed. DNA samples
were available from a panel of 96 unrelated normal control subjects to determine
whether any changes occurred in the general population.
RESULTS
The results are summarized in Table
2 and Table 3. Fifty-seven
cases were familial and 44 were sporadic. There were no differences in the
mean ages at onset for the familial and sporadic cases. Eighteen of the familial
cases and 14 of the sporadic cases had autopsies, 22 of which showed some
form of tau pathologic changes. Twenty cases had neurofibrillary tangles and
9 had Pick bodies. Six tau mutations were discovered in the total group (6/101;
5.9%), the most common of which was P301L (proline-to-leucine substitution
at nucleotide 301) (3/6). Other mutations were L284L (leucine-to-leucine silent
substitution at nucleotide 284), S305N (serine-to-asparagine substitution
at nucleotide 305), and E10 + 16 (nucleotide substitution at position +16
in intron 10). The detailed descriptions of these families have been reported
elsewhere.4, 12, 13, 14, 15
Fifty-seven patients had a positive family history of dementia in at least
1 first-degree relative, and all 6 tau mutations came from this group (10.5%).
No tau mutations were found in the 44 sporadic cases. There were 4 tau mutations
in the familial cases with neuropathologic features (22%), and all 4 came
from the familial group with tau pathologic features (4/12; 33%). Of all 22
cases in the total familial and sporadic groups with tau pathologic features
at autopsy, 4 (18%) were found to have tau mutations. None of the 9 sporadic
cases with Pick bodies and none of the 8 cases of dementia lacking distinctive
histopathologic features had tau mutations.
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Table 2. Tau Mutations in 101 Index Cases With FTD or Non-AD Dementia*
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Table 3. Six Families With Tau Mutations*
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Table 4 lists the 22 normal
polymorphisms found in the tau gene in the control samples. Nine of these
polymorphisms have been previously published and 13 are new. This list will
be of value to other investigators searching for mutations in tau.
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Table 4. Polymorphisms in the Tau Gene*
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COMMENT
These results demonstrate that mutations in the tau gene are a relatively
uncommon cause of FTD and non-AD, nonvascular dementia in a neurology referral
population. The frequency of mutations in this population is approximately
6%, and all were found in subjects with a positive family history. Frontotemporal
dementia can be familial (45% in the study by Chow et al18).
A positive family history of dementia and/or evidence of tau-related neuropathologic
features greatly increases the probability of a tau mutation (10% to 30%).
However, even familial cases and cases with tau pathologic features may not
have demonstrable mutations.
One caveat concerning these results is that no group, including our
own, has performed a complete exhaustive screen of the entire tau gene including
all regulatory, noncoding, and intronic regions. It is conceivable that rare
disease-related mutations lie in these regions, but the number of such mutations
is likely to be small. One possible example of this phenomenon is the hereditary
dysphasic dementia 2 (HDD2) family linked to chromosome 17 but having no demonstrable
tau mutation.19 The tau gene has a large number
of polymorphisms (Table 4) that
occur fairly frequently in the general population and are not likely to be
disease related, but may be difficult to interpret in small focused studies.
One exception appears to be the A0 polymorphism, which shows a consistent
and significant association with progressive supranuclear palsy.20
Even though no tau mutations have yet been found in a sporadic case
of FTD, an occasional case is likely to be discovered. The most common explanations
for such a phenomenon would be nonpaternity, a new mutation, decreased penetrance
in other family members, or early presymptomatic death of a mutation-carrying
parent.21
Our results are similar to those of Houlden et al,8
who evaluated cases from Minnesota and the United Kingdom. They, too, found
no mutations in sporadic non-AD cases and a 9.4% to 13.6% frequency of mutations
in cases with tau pathologic features. Rizzu et al7
found a higher frequency of tau mutations in an FTD population in the Netherlands
(17.8% overall and 43% in the familial cases). These latter results may reflect
the presence of a few large families with FTD linked to chromosome 17 in the
relatively small population of the Netherlands. Nevertheless, all investigators
have documented many FTD cases without tau mutations.
These results have important practical implications. Neurologists and/or
clinical laboratories screening patients with dementia for tau mutations will
have a low yield of positive results, unless there is a strong family history
of dementia and tau-related neuropathologic findings. However, discovering
a patient with a tau mutation has utmost importance to the family in providing
genetic counseling.
Mutations in the tau gene appear to cause neuronal dysfunction and death
by at least 2 mechanisms.22, 23
One is by altering the ability of tau to bind microtubules. The other is by
altering the normal 1:1 ratio of 3 repeat and 4 repeat tau by abnormal splicing
of exon 10. Both types of mutations were found in the present study (Table 3). The abnormal microtubule binding,
perturbed isoform ratio, and cytoplasmic protein aggregation produce a delayed-onset,
progressive dementing illness, but the pathogenesis of this disorder requires
much further investigation.
Finally, the relationship of tau gene mutations to the pathogenesis
of AD remains intriguing. Most brains from cases with tau mutations have no
amyloid plaque pathologic features, but there have been a few exceptions,
including 1 of the cases in this series (family LKL, reported previously).14, 24, 25 Because AD, by definition,
has tau pathologic findings (neurofibrillary tangles), the interactions between
tau and amyloid require much more attention and elucidation.
We conclude that, although mutations in the tau gene represent a powerful
insight into the pathogenesis of neurodegenerative diseases, the frequency
of such mutations in the general population of non-AD dementia is small. Such
mutations are more common in cases with an FTD phenotype with a positive family
history and neuropathologic evidence of abnormal tau inclusions. There must
be additional causes of the FTD syndrome, including other genes involved in
the familial cases. This evidence of heterogeneity in FTD is remarkably similar
to that found in AD, where 3 genes (amyloid precursor protein and presenilins
1 and 2) cause some instances of early-onset familial cases and there is a
genetic risk factor (apolipoprotein E), but the largest numbers of both familial
and sporadic cases still have no known cause.
AUTHOR INFORMATION
Accepted for publication June 12, 2000.
This study was supported by grants AG05136, AG10124, and AG17586 from
the National Institute on Aging, Bethesda, Md, and Veterans Affairs Medical
Research Funds, Washington, DC.
We thank the following physicians who contributed single cases: Michael
Conneally, PhD; John Ebans, MD; William Jagust, MD; John Kamholz, MD; Andrew
Kertesz, MD; Walter Koroshetz, MD; Maureen Leehey, MD; John Morris, MD; David
Munoz, MD; Phillip Swanson, MD, PhD; Armistead Williams, MD; and Minoru Yasada,
MD, PhD.
From the Departments of Medicine (Drs Poorkaj, Schellenberg, and Bird
and Ms Steinbart), Neurology (Drs Schellenberg and Bird), Pathology (Dr Nochlin),
and Psychiatry (Drs Borson, Schellenberg, and Bird), University of Washington,
Seattle; Geriatrics Research Education Clinical Center, Puget Sound Veterans
Affairs Health Care System, Seattle (Drs Poorkaj, Schellenberg, and Bird and
Ms Steinbart); Departments of Neurology and Pathology, University of Pennsylvania,
Philadelphia (Drs Grossman and Trojanowski); Department of Genetics, Oregon
Health Sciences University, Portland (Dr Payami); Department of Medical Genetics,
University of British Columbia, Vancouver (Dr Sadovnick); National Institute
of Neuroscience, Tokyo, Japan (Dr Tabira); Department of Neurology, University
of California, San Diego (Dr Galasko); Department of Neurology, The Johns
Hopkins University School of Medicine, Baltimore, Md (Dr Reich); and Department
of Cognitive Neurology and AD Center, Northwestern University, Chicago, Ill
(Dr Quinn).
Corresponding author and reprints: Thomas D. Bird, MD, Geriatrics
Research Education Clinical Center 182 B, VA Medical Center, 1660 S Columbian
Way, Seattle, WA 98108 (e-mail: tomnroz{at}u.washington.edu).
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