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Genetic linkage of autosomal dominant progressive supranuclear palsy to 1q31.1

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Genetic Linkage of Autosomal Dominant
Progressive Supranuclear Palsy to 1q31.1
Raquel Ros, PhD,1 Pilar Gómez Garre, PhD,2 Michio Hirano, MD,3 Yen F. Tai, MRCP,4
Israel Ampuero, PhD,1 Lı́dice Vidal, PhD,1 Ana Rojo, MD,2 Aurora Fontan, MD,2 Ana Vazquez, MD,2
Samira Fanjul, MD,2 Jaime Hernandez, MD,2 Susana Cantarero, MD,2 Janet Hoenicka, PhD,1
Alison Jones, MD,3 R. Laila Ahsan, MSc,4 Nicola Pavese, MD,4 Paola Piccini, MD,4 David J. Brooks, MD,4
Jordi Perez-Tur, PhD,5 Torbjorn Nyggard, MD,3 and Justo G. de Yébenes, MD, PhD1,2
Progressive supranuclear palsy (PSP) is a disorder of unknown pathogenesis. Familial clusters of PSP have been reported
related to mutations of protein tau. We report the linkage of a large Spanish family with typical autosomal dominant
PSP to a new locus in chromosome 1. Four members of this family had typical PSP, confirmed by neuropathology in one
case. At least five ancestors had similar disease. Other members of the family have incomplete phenotypes. The power of
the linkage analysis was increased by detecting presymptomatic individuals with 18F-fluoro-dopa and 18F-deoxyglucose
positron emission tomography. We screened the human genome with 340 polymorphic markers and we enriched the
areas of interest with additional markers. The disease status was defined according to the clinical and positron emission
tomography data. We excluded linkage to the tau gene in chromosome 17. PSP was linked, in this family, to one area
of 3.4cM in chromosome 1q31.1, with a maximal multipoint < OD score of ⴙ3.53. This area contains at least three
genes, whose relevance in PSP is unknown. We expect to further define the gene responsible for PSP, which could help
to understand the pathogenesis of this disease and to design effective treatment.
Ann Neurol 2005;57:634 – 641
Progressive supranuclear palsy (PSP) is a clinicopathological syndrome characterized by akinesia, supranuclear gaze palsy, rigidity, axial dystonia, gait disturbance, frontolimbic dementia and other clinical deficits
related to neuronal loss, gliosis, and presence of neurofibrillary tangles and neuropil threads in different brain
areas mainly in basal ganglia, diencephalon, brainstem,
and frontal and temporal lobes.1
The cause of PSP is unknown, but it appears to be
most likely multifactorial. Environmental risk factors,
including toxic and infectious agents2–7 or association
with cerebrovascular disease,8,9 long have been recognized, and the disease was considered sporadic until recently, when familial cases were described.10 –15
Since the characteristic histological lesions in the
brains of patients with PSP are immunoreactive to the
tau protein, great interest has arisen about the role of
tau mutations and polymorphisms in the pathogenesis
of PSP. Most patients with mutations of the tau gene
have clinical phenotypes and pathological lesions characteristic of frontotemporal dementia with parkinson-
ism16 that are different from those of typical PSP, but
some families have been reported with clinicopathological characteristics of atypical17–19 or even typical
PSP.20 With respect to tau polymorphisms and haplotypes, it is clear that the risk for PSP is modulated by
the haplotype H1 and H2, which includes a polymorphic dinucleotide repeat, An. The risk for PSP is
greatly reduced in individuals carrying the H2 haplotype as homozygote or even heterozygote.
Genetic analysis of PSP has been hampered by the
lack of familial aggregation of this disorder. This could
be due to the fact that it is a disorder of the elderly,
which strongly reduces the probability of finding a large
enough number of affected individuals available for linkage analysis, although it is not possible to disregard the
possibility of low penetrant genes or an environmental
factor as the causative agent of PSP. Here, we describe a
large Spanish family with pathology-proved PSP. Clinical information was obtained from 45 individuals, and
DNA was taken from 31 family members. To improve
the power of the linkage analysis, we defined the phe-
From the 1Banco de Tejidos para Investigaciones Neurológicas;
2
Fundación Jiménez Dı́az, Universidad Autónoma de Madrid, Madrid, Spain; 3Laboratory of Neurogenetics, Department of Neurology, The Neurological Institute, Columbia University, New York,
NY; 4MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College London, London, United Kingdom; and 5Unitat de
Genètica Molecular, Institut de Biomedicina, Consejo Superior de
Investigaciones Cientı́ficas, Universidad de València, Valencia,
Spain.
Received Nov 1, 2004, and in revised form Jan 4, 2005. Accepted
for publication Feb 4, 2005.
634
Published online Apr 25, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20449
Address correspondence to Dr de Yébenes, Servicio de Neurologı́a,
Fundación Jiménez Dı́az, Avda. de Reyes Católicos 2, Madrid
28040, Spain. E-mail: jgyebenes@fjd.es
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Table 1. Summary of Clinical Findings in Members of the Third Generation of the Family Available for Clinical Evaluation
Patient No.
Characteristic
1
2
3
M/F
F F
M
Age at last visit or 77D 76A 75A
a
death (yr)
Double vision
⫺ ⫺ ⫺
Gaze palsy
⫺ ⫹ ⫺
Blepharospasm
⫺ ⫹ ⫹
AEO
⫺ ⫺ ⫺
SEM
ND ⫹ ⫹
Dysarthria
⫺ ⫺ ⫺
Dysphagia
⫺ ⫺ ⫺
Rigidity
⫺ ⫹ ⫺
Akinesia
⫺ ⫹ ⫺
AAS
⫺ ⫹ ⫺
HPS
⫹ ⫺ ⫺
FO
⫹ ⫺ ⫺
Finger tapping
⫹ ⫺ ⫺
Postural tremor
⫹ ⫹ ⫹
Gait imbalance
⫺ ⫺ ⫺
Frontal dysfunction ⫺ ⫺ ⫺
Facial tics or synki- ⫺ ⫹ ⫹
nesias
Bruxism
⫺ ⫺ ⫺
Improvement with ND ND ND
L-dopa
PET studies
ND A
N
a
4
5
6
7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
F
F
F
M
F
F
M
F
M M M
F
F
F
F
M
F
M
F
F
F
F
M
72A 71A 67A 64A 59A 57A 59D 68A 68A 68D 54A 58A 54A 77A 76A 75A 74D 72D 75A 74A 71A 69A 65A
⫺ ⫺
⫺ ⫺
⫺ ⫺
⫺ ⫺
ND ⫺
⫺ ⫺
⫺ ⫺
⫺ ⫺
⫺ ⫺
⫺ ⫺
⫺ ⫺
⫺ ⫺
⫹/⫺ ⫹/⫺
⫹ ⫺
⫺ ⫺
⫺ ⫺
⫺ ⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫹
⫺ ⫺ ⫺
⫹
⫹
⫺ ⫺ ⫺
⫹
⫹
⫺ ⫺ ⫺
⫹
⫺
⫺ ⫺ ⫺
⫹
⫹
⫺ ND ⫺ ND ND
⫺ ⫺ ⫺
⫹
⫹
⫺ ⫺ ⫺
⫹
⫹
⫺ ⫺ ⫺
⫹
⫹
⫺ ⫺ ⫺
⫹
⫹
⫺ ⫺ ⫺
⫹
⫹
⫺ ⫺ ⫺
⫹
⫹
⫺ ⫺ ⫺
⫹
⫹
⫺ ⫹/⫺ ⫹/⫺ND⫹ ⫹
⫹ ⫺ ⫹
⫹
⫹
⫺ ⫺ ⫺
⫹
⫹
⫺ ⫺ ⫺
⫹
⫹
⫹ ⫺ ⫺
⫹
⫺
⫺ ⫺ ⫺ ⫹ ⫺ ⫺
ND ND ND ND ND ND
N
N
A
N
N
N
⫹
⫹
⫺
⫹
ND
A
⫺
⫹
⫺
⫺
⫹
⫺
⫺
⫹
⫹
⫹
⫺
⫺
⫺
⫺
⫹
⫹
⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫹ ND ND ND ND
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫹ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
ND ND ⫹/⫺ ⫺ ⫹/⫺ ⫹/⫺ ⫹/⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫹
⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺
ND ND ND ND ND ND ⫹
⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫹
⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺
⫹
⫺
⫺ ⫺ ⫺ ⫺ ⫹
⫹
⫺
⫺ ⫺ ⫺ ⫺ ⫹
⫹
⫺
⫺ ⫺ ⫺ ⫺ ⫹
⫹/⫺ ⫺
⫺ ⫺ ⫹ ⫺ ⫹
⫹/⫺ ⫺
⫺ ⫺ ⫹ ⫺ ⫹
⫹/⫺ ⫹/⫺ ⫹/⫺ ⫹/⫺ ⫹/⫺ ⫹/⫺ ⫹/⫺
⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺
⫹
⫺
⫺ ⫺ ⫺ ⫺ ⫹
⫹
⫹
⫺ ⫺ ⫺ ⫺ ⫹
⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺
⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺
⫺
⫺ ⫺ ⫺ ⫺
ND ND ND ND ND ND ND ND ND ND ND ND ND ND
A
ND ND Glu
A
ND ND ND ND ND ND
N
NDNDD
⫺
⫹
A
A after age indicates age at last visit; D indicates age at death.
AEO ⫽ Apraxia eye opening; SEM ⫽ slow eye movement (quantitative evaluation); AAS ⫽ asymmetric arm swing; HPS ⫽ hand pronosupination; FO ⫽ finger opposition; F ⫽ female; M ⫽ male; ND ⫽ not done or not determined; ⫹ ⫽ present or positive; ⫺ ⫽ negative or
absent; N ⫽ normal; A ⫽ abnormal; Glu ⫽ frontal glucose hypometabolism but normal 18-F-dopa uptake; PET ⫽ position emission
tomography.
notype not only by the presence of clinical symptoms,
but also based on the results of 18F-fluoro-dopa (18Fdopa) and 18F-deoxyglucose positron emission tomography (PET) scans performed in members of the family.
Using these tools, we could identify in this family linkage of PSP to a novel locus to 1q31.1.
Subjects and Methods
Subjects
The diagnosis of PSP required either (1) pathology-proved
diagnosis according to international criteria,21,22 or (2) the
presence (Table 1) of the international clinical research criteria for the diagnosis of PSP.23 In some cases, analyzed retrospectively, with insufficient details in the available history
to fulfill the international clinical research criteria, the diagnosis of PSP was accepted if the patients had at least five of
the seven most common clinical symptoms of the disease
(bradykinesia, gait disturbance, supranuclear gaze palsy, dysphagia, dysarthria, axial dystonia, or disabling mental
changes with frontosubcortical characteristics), as described
in a recent clinicopathological series.24 The presence of these
signs was determined clinically. Supranuclear gaze palsy was
defined by saccades smaller than 15 degrees in the vertical or
horizontal plane. Whenever possible, in patients treated at
Fundación Jiménez Dı́az, supranuclear gaze palsy was confirmed by oculonystagmographic analysis. Abnormal oculonystagmographic findings were defined by latency, velocity,
or accuracy of saccadic movements more than 2 standard deviations away from the mean for that age group. Review of
medical records, professional or domestic videos, photographs, samples of hand writing, telephone calls, and visits to
the homes of the patients and relatives were undertaken by
members of the research team when needed to evaluate secondary cases.
When the available information was insufficient to fulfill
the clinical research criteria for the diagnosis of PSP, but it
was suggested by the relatives by a description of the phenotype as “similar” or “the same” as the proband, the individual
was diagnosed as “likely PSP” and included in the analysis as
affected. Individuals diagnosed with other neurological disorders such as tics, tremor, dementia, among others were considered as such and were not diagnosed with PSP.
We obtained information about all available or deceased
first- and second-degree relatives (parents, brothers, sisters,
uncles, cousins) of the proband whenever it was possible.
Neuroimaging
The PET studies were performed at MRC Clinical Sciences
Centre, Hammersmith Hospital (London, United Kingdom). From 1996 to 1997, 10 members of the kindred (indicated with a letter ‘a’ in Table 2) underwent 18F-dopa and
18
F-deoxyglucose PET to measure presynaptic dopaminergic
functions and cerebral glucose metabolism, respectively. The
methods and results for these 10 subjects have been published previoulsly.25 A further five subjects (indicated with
letter ‘b’ in Table 2), including one who had normal scan
results in 1996 (Subject 17), underwent an 18F-dopa scan in
2003. This study was performed using an ECAT EXACT
HR⫹⫹ (CTI/Siemens 966; Siemens Medical Systems,
South Iselin, NJ) PET scanner. All subjects were given
150mg carbidopa 1 hour before the injection of 111MBq
18
F-dopa. All subjects also underwent volumetric T1 magnetic resonance imaging.
Ros et al: PSP Locus
635
Table 2. Positron Emission Tomography Findings of the 14 Members of the Kindred
Subject
No.
Age at the
time of
scan (yr)
Clinical
Findings at the
Time of Scan
Caudate 18F-dopa
Ki
Putamen 18F-dopa
Ki
2a
71
Normal
Abnormal
Abnormal
3a
4b
5a
6a
70
74
67
62
Tremor
Normal
Normal
Tremor
Normal
Normal
Normal
Abnormal
Normal
Normal
Normal
Abnormal
7a
9b
10b
12a
59
60
58
60
Normal
Normal
Normal
PSP
Normal
Normal
Normal
Abnormal
Normal
Normal
Normal
Abnormal
13b
16a
17a,b
62
52
i)48
ii)55
65
57
Akinesia
Normal
Normal
Normal
Normal
Normal
Abnormal
Normal
Normal
Normal
Normal
Abnormal
Abnormal
Normal
Normal
Right putamen abnormal
Normal
Abnormal
24a
27a
Caudate and putaminal
Cerebral Glucose
Metabolism
Frontal and striatal hypometabolism
Normal
NA
Normal
Frontal and striatal hypometabolism
Normal
NA
NA
Frontal and striatal hypometabolism
NA
Frontal hypometabolism
NA
Normal
Frontal and striatal hypometabolism
18
F-DOPA Ki values are considered abnormal if they are more than 2 standard deviations below normal means.
a
Subjects studied in 1996/1997.25
b
Subjects studied in 2003. Subject 17 was studied twice.
NA ⫽ not available.
The 18F-dopa influx rate constants (Ki) parametric images
were generated using a multiple time graphical analysis approach26 with an occipital reference tissue input function.
Each individual’s parametric images then were coregistered
to their respective volumetric magnetic resonance images.
Striatal regions of interest were drawn on individual magnetic resonance images, and these then were applied to the
coregistered parametric images to sample the striatal 18Fdopa Ki. The caudate and putaminal 18F-dopa Ki values of
each subject were compared with those of 13 healthy volunteers (age, 66 ⫾ 4.9 years, mean ⫾ SD). The Ki values were
considered abnormal if they were more than two standard
deviations less than the normal group means.
Genotyping
After obtaining informed consent, we took venous blood
samples from affected relatives and some healthy relatives
and spouses. A brain sample was obtained from the proband
at autopsy. Using standard methods,27 we extracted genomic
DNA from peripheral lymphocytes or frozen brain. The
genome-wide linkage scan was performed using 340 markers
from Set CHLC/Weber Human Screening Version 8a RG
(Research Genetics, Carlsbad, CA) and additional markers in
candidates regions. Polymerase chain reactions for all markers were performed using the same protocol. The reaction
was performed in a 10␮l reaction volume, containing
0.266␮M of each primer, 2mM MgCl2, 0.025U/␮l Taq
Gold polymerase, 1X buffer (10mM Tris HCl [pH 8.3],
50mM KCl); 200␮M deoxyadenosine triphosphate, deoxyguanosine triphosphate, and deoxythymidine triphosphate;
2.5␮M ␣ 32P-deoxycytidine triphosphate (3,000Ci/mmol;
636
Annals of Neurology
Vol 57
No 5
May 2005
Amersham Pharmacia Biotech, Piscataway, NJ); and 80ng
genomic DNA. Polymerase chain reaction conditions were
30 cycles of 94°C for 30 seconds, annealing temperature
55°C for 1 minute, and 72°C for 15 seconds. Polymerase
chain reaction products were separated in 6% polyacrylamide
gels, and the size of the bands was visualized in exposed
Kodak XAR-5 radiographic films (Kodak, Rochester, NY).
Linkage Analysis
Two-point linkage analysis was performed using MLINK of
the LINKAGE program, version 5.1.28 We used an autosomal dominant model with 70 to 90% penetrance (this was
calculated considering the mean age of the members of the
family and that PSP prevalence increases with age), and assuming the frequency of the affected allele to be 0.0001. Recombination frequencies for male and female subjects were
assumed to be equal. Marker alleles were considered equally
frequent. Multipoint linkage analysis was performed using
the LINKMAP program28 and with intermarker distances according to the information provided by the Marshfield Center for Medical Genetics database (database information is
available via the internet at http://www.marshfieldclinic.org/
research/genetics). Exclusion of linkage was considered in areas where the LOD score was less than ⫺2, and evidence for
linkage was defined as LOD score greater than ⫹3. Areas of
interest for further enrichment with additional markers were
those that showed a positive LOD score greater than 1 on
two-point linkage or greater than 2 in multipoint linkage.
Fig 1. Family pedigree and haplotype analysis for the most informative markers from region 1q31.1 that show linkage. Gender is
not defined to prevent the identification of presymptomatic individuals.
Results
Clinical and Pathological Findings
The initial clinical and neuropathological findings in
members of this family have been described elsewhere.11,15 After these reports, three family members
(Subjects 1, 12, and 27), who were previously asymptomatic, experienced development of clinical deficits
compatible with PSP. The clinical study has concentrated on the 26 members of Generation III of this
family who we had the opportunity to visit during the
last 10 years (Fig 1). Most visits took place in their
homes (the family has its origin in Extremadura, but
many patients live in Madrid and other cities of Spain,
Europe, and Latin America), not in the hospital setting. In addition to these 26 subjects, we also visited 1
spouse of a member of Generation II and 9 members
of Generation IV; all of these last subjects were
younger than 40 years of age of whom all were asymptomatic.
The most important clinical findings observed in
this family are summarized in Table 1. Some members
of this family had clinical signs that were considered
unrelated to PSP or insufficient for the clinical diagnosis of this disease. For instance, isolated action/postural
tremor was present in seven of nine members of one
branch of this family, but it was known that tremor
was inherited in this part of the family from an ancestor not affected by PSP. Similarly, some members of
this branch of the family, most of them with tremor,
have abnormal facial movements most likely consistent
with facial tics and facial synkinesias.
Abnormalities in the quantitative evaluation of motor function with the Core Assessment Program for Intracerebral Transplantation (CAPIT) test was not useful because they were present primarily in subjects with
clinical evidence of akinesia. Quantitative evaluation of
ocular movements was abnormal in 5 of 11 patients
studied in the hospital setting, but 4 of them had evidence of other ocular abnormalities such as double vision, gaze palsy, blepharospasm, or lid levator inhibition. Frontal lobe dysfunction was present in six
members of the family, with five of them satisfying the
clinical criteria for PSP.
Treatment with L-dopa was given to three members
of the family, and it improved akinesia but not other
deficits such as gait imbalance, ophthalmoplegia, dysarthria, dysphagia, or frontal lobe dysfunction. One patient treated with L-dopa experienced development of
malignant catatonia and died when, after 4 years of
treatment with L-dopa, the treatment was discontinued
Ros et al: PSP Locus
637
Fig 2. 18F-fluoro-dopa (18F-dopa) integrated (ADD) positron emission tomography images of (A) Subject 9 who was asymptomatic
and (B) Subject 13 who had akinesia. Subject 9 had normal striatal 18F-dopa uptake, whereas Subject 13 showed symmetrical
reduction in striatal 18F-dopa Ki.
because he had an intercurrent ileus paralyticus that
was treated with suppression of food and oral medicines, including L-dopa. Another patient, treated with
L-dopa for 12 years, experienced fluctuations.
The neuropathological findings observed in Patient
III-11 have been reported elsewhere.11 In summary,
the patient had typical neuropathological findings of
sporadic PSP including atrophy of the brainstem, cerebellum, and diencephalon with neuronal loss; deposits
of tau-immunoreactive neurofibrillary tangles without
prominent senile plaques in the cortex; and neuronal
loss, gliosis, and moderate-to-severe accumulation of
tangles in the basal ganglia and brainstem.
Positron Emission Tomography Studies
The mean caudate and putaminal 18F-dopa Ki of
healthy volunteers were 0.0136 ⫾ 0.0014 min⫺1
(mean ⫾ SD) and 0.0132 ⫾ 0.0012 min⫺1, respectively. The PET results are summarized in Table 2. In
addition to Subject 12 who had clinical PSP at the time
of the scan, six other subjects also had abnormal striatal
18
F-dopa or 18F-deoxyglucose PET results. Among
them, Subject 13 (Fig 2) had akinesia, whereas Subject 6
had isolated tremor. Subject 17 had a normal 18F-dopa
PET scan in 1996, but a repeat 18F-dopa PET scan in
2003 showed decrease uptake in the right putamen. The
patient currently remains asymptomatic. Subject 27 was
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asymptomatic at the time of the scan, but had since developed clinical signs consistent with PSP.
Linkage Analysis
We performed a genome-wide search using 340 microsatellite markers. Parametric two-point analysis allowed
us to exclude approximately 20% of the human genome including the region where the tau gene maps.29
On the other hand, we detected scores of LOD suggestive of linkage for markers D1S428 (204.5cM;
LOD ⫽ 2.20 at theta ⫽ 0.00 with 90% penetrance)
and D1S1678 (218.4cM; LOD ⫽ 2.82 at theta ⫽
0.00 with 90% penetrance) (Table 3). Genotyping of
additional markers in this area and multipoint calculations yielded a maximum LOD score of 3.53 for the
interval between D1S428 and D1S461 with 90% penetrances (Fig 3). Linkage to marker D1S1678 disappeared with multipoint analysis. The results of the haplotype analysis for this region are shown in Figure 1.
Thus, the genetic locus responsible for the disease in
this pedigree maps to 1q31.1, between markers
D1S238 and D1S2823, a region of 3.4cM.
Discussion
In this article, we report a family with multiple cases of
PSP, whose clinical phenotype was similar to that
found in patients with sporadic PSP (and with patho-
Table 3. Two-Point LOD Score between the Family in This Study and Markers on Chromosome 1
Recombination Fraction (␪m ⫽ f)
Marker
90% Penetrance
D1S518
D1S238
D1S461
D1S428
D1S2823
D1S2668
D1S1678
D1S2773
70% Penetrance
D1S518
D1S238
D1S461
D1S428
D1S2823
D1S2668
D1S1678
D1S2773
cM
0.0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
202.0
202.0
204.5
204.5
205.4
218.4
218.4
220
⫺5.39
⫺2.47
1.79
2.20
⫺2.43
⫺2.71
2.82
⫺5.17
⫺2.43
⫺2.18
1.56
1.91
⫺1.11
⫺0.76
2.54
⫺0.26
⫺1.36
⫺1.56
1.33
1.62
⫺0.74
⫺0.32
2.25
0.14
⫺0.74
⫺1.09
1.11
1.33
⫺0.50
⫺0.13
1.95
0.29
⫺0.36
⫺0.77
0.91
1.06
⫺0.32
⫺0.04
1.64
0.34
⫺0.13
⫺0.52
0.73
0.81
⫺0.20
⫺0.00
1.33
0.32
0.01
⫺0.33
0.55
0.59
⫺0.10
0.01
1.01
0.27
0.07
⫺0.19
0.39
0.40
⫺0.05
0.01
0.70
0.19
0.08
⫺0.09
0.24
0.24
⫺0.01
0.00
0.41
0.10
202
202
204.5
204.5
205.4
218.4
218.4
220
⫺4.86
⫺1.59
1.72
2.12
⫺1.79
⫺1.83
2.74
⫺4.90
⫺2.17
⫺1.57
1.49
1.84
⫺0.83
⫺0.77
2.47
⫺0.26
⫺1.35
⫺1.25
1.27
1.56
⫺0.58
⫺0.35
2.18
0.14
⫺0.77
⫺0.91
1.05
1.27
⫺0.41
⫺0.16
1.89
0.30
⫺0.40
⫺0.65
0.86
1.01
⫺0.29
⫺0.06
1.59
0.34
⫺0.17
⫺0.45
0.68
0.76
⫺0.18
⫺0.02
1.28
0.32
⫺0.02
⫺0.30
0.51
0.55
⫺0.10
⫺0.00
0.97
0.27
0.05
⫺0.18
0.36
0.37
⫺0.05
0.00
0.67
0.19
0.06
⫺0.09
0.22
0.22
⫺0.02
0.00
0.39
0.1
LOD ⫽ logarithm of odds.
logical confirmation in Patient III-11), with a pattern
of transmission compatible with autosomal dominant
inheritance. The number of family members with clinical symptoms was initially enough for linkage analysis
of the locus of the disease, but DNA could not be obtained from all of them because some had already died
and one branch of the family could not be examined,
leaving the original family uninformative. During the
last 10 years we have followed up with the family and
found that some individuals at risk, previously asymptomatic, have experienced development of clinical findings of PSP. Most neurodegenerative disorders have a
variable presymptomatic period with absence of clinical
features but with an underlying and progressive patho
logical process. For this reason, we included those individuals with abnormal neuroimaging results as affected in the genetic analysis of this pedigree. PET
studies indicated low 18F-dopa uptake in the striatum
or reduced glucose metabolism in the frontal lobe of
six members of this family: one symptomatic member,
two asymptomatic members who later experienced development of clinical symptoms, and three members
who are still asymptomatic. This functional definition
of the analysis in phenotype increased the statistical
Fig 3. Result of multipoint linkage analysis of our family, with chromosome 1q31.1 markers illustrating the region of linkage.
Ros et al: PSP Locus
639
power of this family that allowed us to detect linkage
of the PSP phenotype to a region of 3.4cM in chromosome 1, an area of unknown relevance with respect
to genes involved in the pathogenesis of neurodegenerative disorders.
The cause of PSP is unknown. Described initially 40
years ago,1 PSP was considered a sporadic disease until
recently. During the last decade, several welldocumented familial cases have been reported,10 –15
and genetic risk factors have been described in sporadic
cases, suggesting that the cause of this clinicopathological syndrome could be multiple and multifactorial.
With respect to the genetic risk factors, a case–control
study by means of questionnaires answered by 50 patients indicated a greater prevalence of parkinsonism
(odds ratio, 5.0) and dementia (odds ratio, 3.6) among
first-line relatives of PSP patients30; however, because
of the small size of the cohort, the difference was not
significant.
Some reports31,32 describe a greater prevalence of
the A0 allele, a part of the H1 haplotype of the tau
gene, in patients with sporadic PSP than in the general population. Higgins and colleagues33 confirm
these data and suggest that familial PSP could be inherited as an autosomal recessive disorder linked to
the tau gene. These observations are interesting because the pathological lesions found in the brain of
patients with PSP are immunoreactive to tau protein.
The meaning of that finding, however, is difficult to
interpret because homozygosity for the A0 polymorphism occurs in about 55% of people, whereas the
prevalence of PSP, even in elderly individuals, is only
70 in 100,000 people.34 Furthermore, no linkage has
been found29 in the region 17q 21-22, where the
gene for tau is localized, during a genomic search performed in two informative families included in this
study. In addition, we found that the polymorphism
A0 has similar distribution in affected and nonaffected members of these families,29 and no evidence
of linkage between the PSP phenotype and the gene
for tau was found when analyzing the data with either
an autosomal dominant or autosomal recessive mode
of inheritance in these families.
More interesting is that in a number of cases with
familial PSP-like syndromes, different mutations of exons 1 and 9 through 13 of the tau gene have been reported.17–20,35 In some of these families, the clinicopathological outlook is intermediate between that typical
of PSP and that of tau-related frontotemporal dementia,
whereas in another family,20 the clinicopathological features are indistinguishable from those of typical PSP.
This latter family is interesting because the disease is
caused by a novel mutation of tau, G303V, that increases the ratio of four repeats tau in the patient’s brain.
In our family, mutations of tau have been excluded by
640
Annals of Neurology
Vol 57
No 5
May 2005
linkage analysis and by direct sequencing of exons 1 and
9 through 13 of the tau gene.
In the kindreds previously described with familial
PSP, the apparent pattern of inheritance was variable.15
More than half of these families had affected members
in two or more generations, suggesting autosomal
dominant transmission, but there are families with affected individuals only in the same generation. Consanguinity rarely was seen. Considering the difficulties
in making the diagnosis, primarily in previous generations, it is likely that the disease is more often transmitted as an autosomal dominant disorder.
In addition to tau, other genes could play a role in
PSP. A patient with pathology-proved PSP was found
to be a heterozygous carrier of a C212Y mutation of
the Park-2 gene, as well as a homozygote for the H1
haplotype of tau.36 That report provides an interesting
link between parkin, a protein with ubiquitin ligase
function that plays a role in the processing of tau, and
tauopathies, and it offers an explanation for the increased prevalence of parkinsonism in relatives of patients with Parkinson’s disease.36
The locus associated with PSP in the family that we
describe here is different from any other region of the
human genome involved in PSP or in other related neurodegenerative disorders. The segregation of haplotypes
in this family localizes the locus of PSP to 1q31.1, a
region of 3.4cM that is not fully investigated. The putative genes included in this region are DBCCR1-like,
ENSG00000185167, and ENSG00000162670. DBCCR1 is a gene that is expressed in some human cancers. In human tissues, its maximal expression takes
place in the brain; notably, it is an homologue of
BMP/retinoic acid-inducible neural specific protein 3
(Brinp3). Retinoic acid plays a role in the differentiation of several neuronal phenotypes, including dopamine and cholinergic neurons, and it modulates the
survival of dopamine neurons in vitro.37 Little is
known about the other putative genes, with the exception that ENSG00000162670 also is expressed in
the brain.
Even if the cause of PSP is multifactorial, finding the
gene responsible for the disease in this family would help
to understand the pathogenesis of the disease in other
cases, because the mechanisms responsible for the brain
lesions in all patients with PSP should have a common
final pathway. Finding more affected individuals of this
kindred would increase the chances of cloning the responsible gene if there were individuals with recombinations that restrict the area of linkage. In addition, we
hope that with the help of other small kindreds with
familial PSP the area of linkage could be further reduced
and the gene and the protein responsible for this disease
identified. If the function of the responsible protein is
understood, then it will be easier to design rational therapeutic targets for this disease.
This study was supported by grants from the Society for Progressive
Supranuclear Palsy (USA), the Progressive Supranuclear Palsy Association (Europe), Fundacion Areces, Comunidad Autónoma de Madrid and ISCIII (Red CIEN, J.G.Y.), and Fondo de Investigaciones
Sanitarias (grant BAE 98/5039, A.R.).
We acknowledge the generous helpful suggestions provided by Drs
S. Rodriguez de Cordobaand and J. Serratosa during the performance of the linkage study and also their useful ideas while reading
the manuscript.
References
1. Steele J, Richardson J, Olszewski J. Progressive supranuclear
palsy. Arch Neural 1964;10:333–359.
2. Jellinger K. Progressive supranuclear palsy: subcortical argyrophilic dystrophy. Acta Neuropathol (Berl) 1971;19:347–352.
3. Steele JC. Progressive supranuclear palsy. Brain 1972;95:
693–704.
4. Steele J. Progressive supranuclear palsy. In: Vinken PH, Bruyn
GW, ed. Handbook of clinical neurology. Amsterdam: NorthHolland, 1975:217–229.
5. Kristensen MO. Progressive supranuclear palsy—20 years later.
Acta Neurol Scand 1985;71:177–189.
6. Lilienfeld D, Perl D, Olanow W. Guam neurodegeneration. In:
Calne DB, ed. Neurodegenerative diseases. Philadelphia: WB
Saunders, 1994:895–908.
7. Jendroska K, Hoffmann O, Schelosky L, et al. Absence of disease related prion protein in neurodegenerative disorders presenting with Parkinson’s syndrome. J Neurol Neurosurg Psychiatry 1994;57:1249 –1251.
8. Dubinsky RM, Jankovic J. Progressive supranuclear palsy and a
multi-infarct state. Neurology 1987;37:570 –576.
9. Winikates J, Jankovic J. Vascular progressive supranuclear palsy.
J Neural Transm Suppl 1994;42:189 –201.
10. Brown J, Lantos P, Stratton M, et al. Familial progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1993;56:
473– 476.
11. de Yebenes JG, Sarasa JL, Daniel SE, Lees AJ. Familial progressive supranuclear palsy. Description of a pedigree and review of
the literature. Brain 1995;118:1095–1103.
12. Golbe L, Dickson D. Familial autopsy-proven progressive supranuclear palsy. Neurology 1995;45(suppl 4):A255.
13. Tetrud J, Golbe L, Forno L, Farmer P. Autopsy-proven progressive supranuclear palsy in two siblings. Neurology 1996;46:
931–934.
14. Lanotte L, Barroche G, Taillandier L, Lacour J. Familial progressive supranuclear palsy. Mov Disord 1996;11(suppl 1):P461.
15. Rojo A, Pernaute RS, Fontan A, et al. Clinical genetics of familial
progressive supranuclear palsy. Brain 1999;122:1233–1245.
16. Wilhelmsen KC, Lynch T, Pavlou E, et al. Localization of
disinhibition-dementia-parkinsonism-amyotrophy complex to
17q21–22. Am J Hum Genet 1994;55:1159 –1165.
17. Stanford PM, Halliday GM, Brooks WS, et al. Progressive supranuclear palsy pathology caused by a novel silent mutation in
exon 10 of the tau gene: expansion of the disease phenotype
caused by tau gene mutations. Brain 2000;123:880 – 893.
18. Pastor P, Pastor E, Carnero C, et al. Familial atypical progressive supranuclear palsy associated with homozigosity for the
delN296 mutation in the tau gene. Ann Neurol 2001;49:
263–267.
19. Poorkaj P, Muma NA, Zhukareva V, et al. An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. Ann Neurol 2002;52:511–516.
20. Ros R, Thobois S, Streichenberger N, et al. A new mutation of
the tau gene, G303V, in early onset familial progressive supranuclear palsy. Arch Neurol (in press).
21. Hauw JJ, Daniel SE, Dickson D, et al. Preliminary NINDS
neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 1994;44:
2015–2019.
22. Litvan I, Hauw JJ, Bartko JJ, et al. Validity and reliability of
the preliminary NINDS neuropathologic criteria for progressive
supranuclear palsy and related disorders. J Neuropathol Exp
Neurol 1996;55:97–105.
23. Litvan I, Mangone CA, McKee A, et al. Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) and clinical predictors of survival: a clinicopathological
study. J Neurol Neurosurg Psychiatry 1996;60:615– 620.
24. Daniel SE, de Bruin VM, Lees AJ. The clinical and pathological
spectrum of Steele-Richardson-Olszewski syndrome (progressive
supranuclear palsy): a reappraisal. Brain 1995;118:759 –770.
25. Piccini P, de Yebenez J, Lees AJ, et al. Familial progressive supranuclear palsy: detection of subclinical cases using 18FDOPA and 18fluorodeoxyglucose positron emission tomography. Arch Neurol 2001;58:1846 –1851.
26. Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain
transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 1985;5:584 –590.
27. Sambrook J, Fritsch K, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. New York: Cold Spring Harbor Laboratory Press, 1989.
28. Lathrop GM, Lalouel JM, Julier C, Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A
1984;81:3443–3446.
29. Hoenicka J, Perez M, Perez-Tur J, et al. The tau gene A0 allele
and progressive supranuclear palsy. Neurology 1999;53:
1219 –1225.
30. Davis PH, Golbe LI, Duvoisin RC, Schoenberg BS. Risk factors for progressive supranuclear palsy. Neurology 1988;38:
1546 –1552.
31. Conrad C, Andreadis A, Trojanowski JQ, et al. Genetic evidence for the involvement of tau in progressive supranuclear
palsy. Ann Neurol 1997;41:277–281.
32. Lazzarini A, Golbe L, Dickson D, et al. Tau intronic polymorphism in Parkinson’s disease and progressive supranuclear palsy.
Neurology 1997;(suppl 2):P06.088.
33. Higgins JJ, Litvan I, Pho LT, et al. Progressive supranuclear
gaze palsy is in linkage disequilibrium with the tau and not the
alpha-synuclein gene. Neurology 1998;50:270 –273.
34. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence of progressive supranuclear palsy and multiple system
atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 1997;49:1284 –1288.
35. Hayashi S, Toyoshima Y, Hasegawa M, et al. Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene
mutation. Ann Neurol 2002;51:525–530.
36. Morales B, Martinez A, Gonzalo I, et al. Steele-RichardsonOlszewski syndrome in a patient with a single C212Y mutation
in the parkin protein. Mov Disord 2002;17:1374 –1380.
37. Mena MA, Casarejos MJ, Bonin A, et al. Effects of dibutyryl
cyclic AMP and retinoic acid on the differentiation of Dopamine neurons: prevention of cell death by dibutyryl cyclic
AMP. J Neurochem 1995;65:2612–2620.
Ros et al: PSP Locus
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