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Association of Moderate Polyglutamine Tract Expansions in the Slow Calcium-Activated Potassium Channel Type 3 With Ataxia
Karla Patricia Figueroa, MS;
Piu Chan, MD, PhD;
Ludger Schöls, MD;
Carline Tanner, MD, PhD;
Olaff Riess, MD;
Susan L. Perlman, MD;
Daniel H. Geschwind, MD, PhD;
Stefan M. Pulst, MD
Arch Neurol. 2001;58:1649-1653.
ABSTRACT
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Background The small-conductance calcium-activated potassium channel gene (hSKCa3) contains 2 CAG repeats, 1 of which is highly polymorphic.
Although this repeat is not pathologically expanded in patients with schizophrenia,
some studies have suggested an allelic association with schizophrenia. CAG
expansions in other genes such as the  1 subunit of a brain-specific
P/Q-type calcium channel gene cause spinocerebellar ataxia type 6, whereas
the length of the CAG repeat in the RAI1 gene modifies
the age of onset of spinocerebellar ataxia type 2.
Objectives To evaluate expansions in the hSKCa3 polyglutamine
domain as causative for ataxia, and to study the association between the length
of the polyglutamine repeat and the presence of ataxia.
Methods We analyzed this repeat in 122 patients with autosomal dominant cerebellar
ataxia, or sporadic ataxia, and compared allele distribution with 750 alleles
seen in 2 healthy control groups and 172 alleles in patients with Parkinson
disease.
Results The distribution of alleles in ataxia patients and controls was significantly
different by Wilcoxon rank test (P<.001). Twenty-two
or more polyglutamine tracts were more common in ataxia patients compared
with controls by  2 analysis (P<.001).
Conclusion Longer stretches of polyglutamines in a human potassium channel are
not causative for ataxia, but they are associated with the presence of ataxia.
There is no association with the presence of Parkinson disease.
INTRODUCTION
DESPITE THE identification of 6 spinocerebellar ataxia (SCA) genes,
20% to 50% of autosomal dominant cerebellar ataxia (ADCA) mutations are still
unaccounted for. The molecular basis of late-onset sporadic ataxias, sometimes
also referred to as olivo-ponto-cerebellar atrophies, has remained largely
unexplained because mutations in known genes are very rare in patients without
a positive family history and involve mutations in the SCA1, SCA2, or Friedreich ataxia gene.1, 2, 3, 4 Only
expansions in the SCA6 repeat are found in appreciable
numbers in patients with sporadic ataxia. In one study, a third of patients
with a repeat expansion in the SCA6 gene had no family
history of the disorder.5, 6
The SCA6 mutation is distinct in several respects.
The polyglutamine tract is located in the 1 subunit of a brain-specific
P/Q-type calcium channel. Nonsense and missense mutations in this channel
occur as well, and are associated with episodic ataxia type 2 and familiar
hemiplegic migraine, respectively.7 The range
of expansion seen on chromosomes of affected patients with SCA6 is 21 to 27
repeats—smaller than in any of the other genes. Expanded repeats do
not exhibit the marked meiotic instability that is typical of other CAG-repeat
diseases.
Recently, a novel, small-conductance calcium-activated potassium channel
gene (hSKCa3) was identified that has 2 CAG repeats
in its coding region.8 The first of these repeats
is not very polymorphic. It ranges in size from 5 to 12 repeats, with 12 being
the most common; the second repeat is highly variable, with alleles containing
7 to 28 repeats and the modal containing 19 repeats. The hSKCa3 gene was initially mapped to a region of human chromosome 22,
which is thought to contain genes predisposing individuals to schizophrenia.
Owing to this map position, the allele distribution in healthy controls and
patients with schizophrenia was extensively studied. Allele distribution seemed
to be differentially distributed between the 2 samples, with patients with
schizophrenia having slightly larger alleles.8
However, no allele class was unique to the schizophrenia sample, and subsequent
reports differed in the strength of allelic association with schizophrenia.8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21
The polymorphic hSKCa3 repeat seemed to be
a good candidate for expansion in patients with ADCA. The most common alleles
were similar in range of size as those alleles in other SCA genes. Furthermore,
the repeat was a perfect CAG repeat not stabilized by the interruptions observed
in SCA1 and SCA2. Based on expansions in SCA6, we predicted that the disease-causing
expansions would be relatively minor and that, in addition to patients with
ADCA, patients without apparent family history would need to be examined.
MATERIALS AND METHODS
GENOTYPE ANALYSIS
Genotyping was performed according to the method used for the European
part of the study described in Chandy et al.8
European primers were used to amplify both repeats. The following nested primers
were designed to amplify each repeat independently. For the first repeat "forward":
3A 5'-GGGTGGGGACTTGGATGAA-3'
and "reverse"
3B 5'-GCTGAAGCTGCGGAGGCTGAG-3'
generated a 170–base pair (bp) fragment when 12 repeats are present.
For the second repeat "forward":
2A 5'-GCCTCAGCCTCCGCAGCT-3'
and "reverse"
2B 5'-GGACGGGCTGGCTCTGGA-3'
generated a 110-bp fragment at 14 repeats. Polymerase chain reaction
conditions for both primers were initial denaturation at 95°C for 5 minutes,
35 cycles at 95°C for 1 minute and 30 seconds, 62°C for 30 seconds,
72°C for 45 seconds, and a final extension at 72°C for 5 minutes.
Polymerase chain reaction products were analyzed using a 6% polyacrylamide
gel with an M13 ladder as a size marker. Samples were also selected from all
gels and run on a single gel as an additional check that all allele sizes
were consistently scored between runs.
The sizes of the resulting polymerase chain reaction products were then
analyzed as described earlier. Twenty samples ranging in repeat size from
5 to 12 for the first repeat, and 10 to 23 for the second repeat were sequenced
in an ABI373 DNA sequencer (PE Corp, Foster City, Calif) to serve as size
controls.
To address the possibility that the presence of multiple affected individuals
from single nuclear families may produce false-positive results, a single
affected individual per family was chosen at random.
STATISTICAL ANALYSIS
Data were analyzed by Wilcoxon rank test and by performing an overall 2 test with the appropriate degrees of freedom. Comparisons were made
for allelic distribution and for distribution of genotypes.
With regard to chromosome localization, mapping of hKCa3 was performed using the GeneBridge 4 panel,22
consisting of 93 radiation hybrid clones (Research Genetics, Huntsville, Ala)
and primers 2A and 2B as previously described. Results were submitted to the
Whitehead Institute Genome Center server (http://www.genome.wi.mit.edu).
RESULTS
MAPPING OF hSKCa3
We performed radiation hybrid mapping using the GeneBridge 4 panel.
Results indicated that hSKCa3 maps to chromosome
1q21 with a lod score of 1.46. The gene resides between markers D1S305 and
IB1251, at a distance of 2.63 centiray from D1S305.
ALLELIC ASSOCIATION
We examined 24 patients representing 20 families with ADCA, as well
as 98 patients who did not have an apparent family history of ataxia. None
of these patients were positive for a mutation in SCA1, SCA2, SCA3, SCA6,
or SCA7. The hKCa3 gene encodes a protein of 731 amino acids containing 2
adjacent polyglutamine arrays in its N-terminal domain, separated by 25 amino
acids. The 5' CAG repeat was not highly polymorphic, with a major allele
of 12 repeats accounting for 97.9% of alleles. Alleles with 5, 7, and 10 repeats
made up 1.5%, 0.1%, and 0.5%, respectively.
The 3' CAG repeat was highly polymorphic. The allele distribution
for the 3' CAG repeat in patients with ataxia is shown in Figure 1. The most common allele contained 19 repeats, followed
in frequency by alleles of 18 and 20 repeats. A bimodal character was evident
in the distributions, with a smaller peak present at 12 to 15 repeats, as
has also been reported in 2 previous studies.8, 11
Only 1 of the 122 patients had an allele size that was in a range not previously
reported for healthy individuals or patients with a history of psychiatric
illness. This sporadic ataxia patient had 1 allele with 28 repeats and a second
allele with 19 repeats. A search for additional patients with ataxia who carry
alleles of this size range or larger yielded negative results, except for
1 patient with a known SCA6 mutation who had an hSKCa3
allele of 27 repeats.
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Figure 1. Allele distribution of the 3'CAG
repeat in the human hSKCa3 gene. Data for patients
with ataxia are plotted as purple bars, Parkinson disease spouses as red,
healthy octogenarians as yellow, and Parkinson disease patients green.
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Although these observations did not suggest a direct pathogenic role
for long hSKCa3 alleles, analysis of allele distribution
in patients with ataxia suggested that long alleles were more common than
in previously reported control groups. Whereas alleles with 22 repeats were
much rarer than alleles with 21 repeats in previously reported healthy controls
and psychiatric patients, in patients with ataxia, alleles with 22 repeats
were actually more common than alleles with 21 repeats.
To verify these observations, we examined 2 independent control groups.
The first consisted of 228 chromosomes from spouses of patients with Parkinson
disease (PD) in California. The second control group consisted of 522 chromosomes
from healthy octogenarians from central Europe. Allele distributions for these
groups are shown in Figure 1. There
were no significant differences in the allele distributions between the 2
control groups by Wilcoxon rank test or 2 analysis. Alleles
with more than 22 repeats were rare and represented only 0.8% of spouses with
PD and 0.8% in healthy octogenarians. The longest allele seen on normal chromosomes
contained 25 repeats. We therefore combined both control groups for all subsequent
statistical analyses.
We tested 2 related but distinct hypotheses. We first examined whether
allele distribution for the entire spectrum of allele lengths differed between
patients with ataxia and controls by the Wilcoxon signed rank test. This hypothesis
does not require the presence of the specific threshold mentioned earlier,
in which a disease association is observed. Two-tailed Wilcoxon signed rank
tests determined that allele sizes differed in patients with ataxia (P<.001).
Subsequently, we tested the hypothesis that alleles above a threshold
level of 21 repeats were associated with ataxia. Compared with our 2 healthy
control groups, alleles with 22 or more CAG repeats were almost 5 times as
common and were seen in 4.9% of patients with ataxia. This difference was
statistically significant by 2 analysis (P<.001). Setting the threshold at 21 or more CAG repeats also yielded
significant differences (P<.04), as well as at
a threshold of 23 or more CAG repeats (P<.05).
To examine whether the association of alleles with 22 or more repeats
in patients with ataxia was specific to this form of neurodegeneration, we
examined 172 chromosomes of patients with sporadic PD ranging in age from
30 to 83 years. In patients with PD, alleles with 22 or more CAG repeats had
a frequency of 1.7% (Figure 1).
This frequency was not different from that of controls (P = .26).
GENOTYPIC ASSOCIATION
We also analyzed whether an association with genotype existed in addition
to allelic association. For this analysis we added the CAG repeat numbers
in both alleles and compared the number of genotypes with 40 or more CAG repeats
(Figure 2). By the 2-tailed Wilcoxon
signed rank test, genotypes were different between patients with ataxia and
controls (P<.001). In patients with ataxia, genotypes
with 40 or more summed CAGs were significantly more common than genotypes
in controls (P<.001). Genotypes for patients with
PD were not different than those of controls.
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Figure 2. Distribution of genotypes. Genotypes
were determined by adding repeat units in the 3'CAG repeat in both hSKCa3 alleles. Data for patients with ataxia are plotted
as purple bars, combined control populations as red bars, and Parkinson disease
patients as green.
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COMMENT
The CAG repeat in the hSKCa3 channel represented
a good candidate for pathologic expansion in patients with ataxia or other
neurodegenerative disorders. Expansion of polyglutamine repeats in several
proteins is known to cause neurodegenerative disorders.23
The CAG repeat expansion in another channel protein, the CACNL4A gene, causes SCA6. In addition, a northern blot analysis revealed hKCa3-specific expression to be largely limited to the
brain, striated muscle, and lymphoid tissues.20
Because of conflicting reports regarding chromosomal location, we mapped hSKCa3 using radiation hybrid mapping. Our map position
in chromosome 1q21 does not agree with the initial reports by Chandy et al,21 who had mapped hSKCa3 to
chromosome 22. Our results, however, confirm the report by Austin et al,15 who mapped hSKCa3 to the
identical region by radiation hybrid mapping. This region has been linked
to familial hemiplegic migraine, but not to schizophrenia or other neuropsychiatric
disorders.26
In diseases caused by CAG repeat expansion, a threshold effect can be
detected. Below the threshold, no pathological abnormality is observed, but
above the threshold, expansions invariably cause disease. Length of the abnormal
poly Q tract is strongly associated with age of onset. In some diseases, such
as SCA3 or dentatorubral pallidoluysian atrophy, normal and abnormal repeat
lengths are separated by many repeats, whereas in SCA6 the separation is only
1 repeat. In Huntington disease and SCA2, intermediate alleles are seen that
predispose individuals to disease, and are associated with reduced penetrance.27, 28, 29
Encouraged by the observation of an hSKCa3
allele with 28 repeats in a patient with sporadic ataxia we sought to identify
other patients that had allele sizes not previously reported in healthy controls.
No patients, however, were identified, except for a patient with SCA6 who
had an hSKCa3 allele with 27 repeats. Though to our
knowledge, alleles of this size have not been reported in control populations
analyzed worldwide, an allele with 30 CAG repeats was identified in a Chinese
patient of unspecified age with schizophrenia.9
Results of a neurologic examination of that patient were not reported. Therefore,
it is not likely that long CAG repeats in the hSKCa3
gene are a common cause of ataxia.
Although we could not prove a causative role for large hSKCa3 alleles, inspection of allele distribution in patients with
ataxia suggested that larger alleles were more common in this group than reported
in previous studies examining healthy controls or patients with schizophrenia.
Whereas alleles with 22 or more CAG repeats were seen in less than 1% of controls
or patients with schizophrenia worldwide, 4.9% of patients with ataxia had
alleles with 22 or more CAG repeats, and 1.5% had alleles with 23 or more
CAG repeats. To confirm this observation, we determined allele sizes in 2
control populations. Although ascertained by different methods, both of our
control groups had almost identical allele distributions. Alleles with 22
or more repeats constituted 0.8% of all alleles, whereas alleles with 23 or
more repeats were seen in only 0.2% of normal chromosomes. The allele distribution
in our control group was in perfect agreement with previously published studies
on various ethnic groups (ie, French/Alsatian,8
Chinese,9 Anglo-Saxon,11
Irish,16 and Israeli Jewish17).
Because alleles with 22 or more CAG repeats are rare in healthy controls,
we set this length as a threshold for statistical comparison by 2 analysis. The frequency of alleles with 22 or more CAG repeats was
significantly increased in patients with ataxia. Even when a threshold was
set at an allele size of 21 or more or 23 or more CAG repeats, distribution
of alleles above this threshold was significantly different in patients with
ataxia.
To determine whether large repeats were associated with neurodegenerative
diseases in general, we tested a population of patients with PD, with an age-at-onset
range from 31 to 83 years. The frequency of large alleles in patients with
PD was not different from that seen in our 2 control groups. Further studies
of patients with other neurodegenerative diseases are needed to determine
whether the hSKCa3 CAG polymorphism is indeed specifically
associated with ataxia.
Predisposing alleles may show additive effects when present in the homozygous
state. For example, the presence of an ApoE4 allele
modifies the age at onset of Alzheimer disease, and this effect is more pronounced
in ApoE4 homozygotes.30
An additive effect of pathologically expanded alleles is also seen in mouse
models of SCA131 and SCA2,32
although this is less obvious in rare human cases with alleles homozygous
for repeat expansion. In Huntington disease and other CAG-repeat diseases,
the correlation of age at onset with repeat length of the pathologically expanded
allele is well documented.27 Repeat length
variation of the normal allele seems to contribute relatively little to age
at onset variation in HD or SCA2.33, 34
In SCA2 patients, CAG repeat length in the RAI1 gene
seemed to influence age at onset. This effect was seen for contribution of
the longest allele or for the CAG sum determined by adding the CAG repeats
in both RAI1 alleles.34
To determine whether the genotype at the hSKCa3 locus
was associated with ataxia, we added the number of repeats of both alleles,
assuming a simple additive effect. An association of genotypes with 40 or
more CAG repeats with ataxia was detected, but was not seen in patients with
PD. The number of patients studied, however, was too small to determine whether
this effect was due solely to the presence of a single allele with a very
long CAG repeat.
Association studies can have significant limitations owing to the presence
of population stratification. Allele distribution may vary in different ethnic
or geographic groups. Their differential admixture to study and control populations
may mimic allelic association in the study group. Because of the high interest
in the hSKCa3 polymorphism for psychiatric diseases,
the CAG repeat allele distribution in the hSKCa3
gene has been extensively studied worldwide. No significant differences in
allele distribution in different ethnic groups have been identified.9, 10, 12, 13, 16, 17, 20
This makes it unlikely that our observations are simply caused by population
stratification. Despite this, the results of our study need to be repeated
in other groups of patients with ataxia. If confirmed, it will be important
to analyze whether allelic variation in the hSKCa3
channel is a disease modifier only in patients carrying other highly penetrant
disease alleles at other loci, or whether it modifies an environmental risk
factor. Most importantly, it will be critical to define the effects of long
polyglutamine tracts on channel function and the involvement of this channel
in neurodegeneration. In addition, the possibility remains that the polymorphic
repeat in hKCa3 is merely in linkage disequilibrium
with an as yet unidentified functional polymorphism or a causative mutation
within the gene or in its vicinity.
AUTHOR INFORMATION
Accepted for publication November 17, 2000.
This work was supported by the Carmen and Louis Warschaw Endowment for
Neurology, F.R.I.E.N.D.s of Neurology, a pilot grant from the National Ataxia
Foundation (Drs Perlman and Geschwind) to support the UCLA ataxia research
program, grant R01-NS33123 (Dr Pulst) from the National Institutes of Health,
Bethesda, Md, and a generous donation by the Smith Family in memory of Waverly
Smith (Drs Geschwind and Perlman).
From the Rose Moss Laboratory for Parkinson's and Neurodegenerative
Diseases, Cedars-Sinai Medical Center Burns and Allen Research Institute,
Cedars-Sinai Medical Center, Los Angeles, Calif (Ms Figueroa and Dr Pulst);
the Parkinson Institute, Sunnyvale, Calif (Drs Chan and Tanner); the Department
of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany (Dr
Schöls); the Department of Medical Genetics, Children's Hospital, University
of Rostock, Rostock, Germany (Dr Riess); the Department of Neurology, University
of California Medical School, Los Angeles (Drs Perlman and Geschwind); and
the Division of Neurology, Cedars-Sinai Medical Center, UCLA School of Medicine,
Los Angeles (Dr Pulst).
Corresponding author: Stefan M. Pulst, Division of Neurology, Cedars-Sinai
Medical Center, Los Angeles, CA 90048 (e-mail: pulst{at}cshs.org).
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