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Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2).

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Neuropsychiatric Genetics
Common Origin of Pure and Interrupted Repeat
Expansions in Spinocerebellar Ataxia Type 2 (SCA2)
Eliana Marisa Ramos,1 Sandra Martins,1,2 Isabel Alonso,1 Vanessa E. Emmel,3
Maria Luiza Saraiva-Pereira,3 Laura Bannach Jardim,3 Paula Coutinho,1,4
Jorge Sequeiros,1,5 and Isabel Silveira1*
UnIGENe, IBMC—Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
IPATIMUP—Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
Hospital de Clınicas de Porto Alegre, Porto Alegre, Brazil
Hospital S~ao Sebasti~ao, Feira, Portugal
ICBAS - Instituto de Ci^encias Biomedicas Abel Salazar, Universidade do Porto, Porto, Portugal
Received 16 February 2009; Accepted 25 June 2009
The spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by gait and limb
ataxia. This disease is caused by the expansion of a (CAG)n
located in the ATXN2, that encodes a polyglutamine tract of
more than 34 repeats. Lately, alleles with 32–33 CAGs have been
associated to late-onset disease cases. Repeat interruptions by
CAA triplets are common in normal alleles, while expanded
alleles usually contain a pure repeat tract. To investigate the
mutational origin and the instability associated to the ATXN2
repeat, we performed an extensive haplotype study and sequencing of the CAG/CAA repeat, in a cohort of families of different
geographic origins and phenotypes. Our results showed (1) CAA
interruptions also in expanded ATXN2 alleles; (2) that pathological CAA interrupted alleles shared an ancestral haplotype
with pure expanded alleles; and (3) higher genetic diversity in
European SCA2 families, suggesting an older European ancestry
of SCA2. In conclusion, we found instability towards expansion
in interrupted ATXN2 alleles and a shared ancestral ATXN2
haplotype for pure and interrupted expanded alleles; this finding
has strong implications in mutation diagnosis and counseling.
Our results indicate that interrupted alleles, below the pathological threshold, may be a reservoir of mutable alleles, prone to
expansion in subsequent generations, leading to full disease
mutation. 2009 Wiley-Liss, Inc.
Key words: trinucleotide repeat expansion; polyglutamine;
How to Cite this Article:
Ramos EM, Martins S, Alonso I, Emmel VE,
Saraiva-Pereira ML, Jardim LB, Coutinho P,
Sequeiros J, Silveira I. 2010. Common Origin
of Pure and Interrupted Repeat Expansions in
Spinocerebellar Ataxia Type 2 (SCA2).
Am J Med Genet Part B 153B:524–531.
(tri- or pentanucleotide) repeat; most are due to the expansion of a
(CAG)n, which encodes a toxic polyglutamine tract in the specific
protein. Although very variable among populations, several epidemiological studies estimate the prevalence of inherited ataxias to be
less than six cases per 100,000 persons worldwide [Sequeiros et al.,
in press].
Wadia and Swami [1971] described several families from India,
with ataxia and very slow ocular movements. Several years later, a
form of dominant olivopontocerebellar atrophy was reported in
northeastern Cuba, with a prevalence of up to 500:100,000 in the
province of Holguin [Orozco et al., 1989; Velazquez-Perez et al.,
2001]. This form was later associated to the expansion of a (CAG)n
in the ATXN2 gene, and named SCA2 [Imbert et al., 1996; Pulst
et al., 1996; Sanpei et al., 1996]. Holguin’s ataxia and Wadia and
Swami’s proved to be the same clinical entity [Wadia et al., 1998].
repeat interruptions; ancestral haplotype
Autosomal dominant spinocerebellar ataxias (SCAs) are a clinically
heterogeneous group of neurological degenerative diseases. The
main clinical symptoms are gait and limb ataxia, often accompanied by pyramidal signs, peripheral neuropathy, ophthalmologic,
or cognitive signs. There are, at least, 30 loci known to be implicated
in SCAs. The cause is often the expansion of an oligonucleotide
2009 Wiley-Liss, Inc.
Grant sponsor: Fundaç~ao para a Ci^encia e Tecnologia (FCT); Grant
Numbers: POCI/SAU-MMO/56387/2004, PIC/IC/82897/2007; Grant
sponsor: FEDER.
*Correspondence to:
Isabel Silveira, UnIGENe, IBMC, Rua do Campo Alegre, 823, 4150-180
Porto, Portugal. E-mail:
Published online 12 August 2009 in Wiley InterScience
DOI 10.1002/ajmg.b.31013
The trinucleotide repeat is located in exon 1 of the ATXN2 gene,
on chromosome 12q24.1. In the first reports, normal alleles were
found to range 14–31 repeats and to be stably transmitted, whereas
expanded mutant alleles had over 34 repeat units. More recently,
alleles with 32–33 triplets have been associated to late-onset patients
of SCA2 [Costanzi-Porrini et al., 2000; Fernandez et al., 2000; Kim
et al., 2007]. The repeat has one to four CAA interruptions in
normal alleles, whereas expanded alleles usually contain a pure tract
[Imbert et al., 1996; Pulst et al., 1996; Sanpei et al., 1996; Choudhry
et al., 2001; Sobczak and Krzyzosiak, 2005]. Although these interruptions may not fully prevent the pathogenesis of expanded alleles
(as the CAA triplet encodes also a glutamine), some authors have
proposed that they may enhance its intergenerational stability, by
inhibiting strand slippage [Costanzi-Porrini et al., 2000; Choudhry
et al., 2001].
Recently, ATXN2 expansions have been reported in familial
parkinsonism and even in sporadic parkinsonism [Gwinn-Hardy
et al., 2000; Shan et al., 2004]. These cases show late-onset, slow
progression of symptoms, bradykinesia, rigidity, and sustained
response to L-dopa, and are caused by borderline expansions of
32–43 repeats, interrupted by CAA triplets [Costanzi-Porrini et al.,
2000; Gwinn-Hardy et al., 2000; Shan et al., 2001; Furtado et al.,
2002; Lu et al., 2002].
To investigate the mutational origin and the instability of
ATXN2 alleles, in a cohort of families with different geographic
origins, we characterized the repeat tract configuration and determined the flanking haplotype of normal and expanded chromosomes with intragenic SNPs and microsatellites.
SCA2 Families and Control Population
This study was carried out in 17 unrelated SCA2 families, comprising 51 subjects, including patients and family members, of diverse
ethnic origins, namely Portuguese (7), Brazilian (7), Indian (2), and
Italian-American (1) [Suite et al., 1986; Silveira et al., 2002]. In
addition, six isolated cases of ataxia with alleles of undetermined
significance (31–32 repeats) were included. A total of 77 normal
chromosomes from different geographic origins, including Portuguese, Brazilian, Indian, and Italian were also analyzed. Peripheral
blood samples were collected from patients and healthy individuals
after a written informed consent was obtained. Genomic DNA was
obtained as previously reported [Silveira et al., 2002].
Genotyping and Sequencing
Repeat sizes at the ATXN2 were determined by PCR amplification,
using primers previously described [Pulst et al., 1996]. PCR amplification of markers D12S1333 and D12S1672 was carried out
with 0.6 mM of each primer, 200 mM of dNTPs, 1.5 mM MgCl2,
0.75 U of Taq DNA polymerase (Fermentas, Burlington, Ontario),
and 2% formamide, in a final volume of 25 ml. The size of the
fluorescently labeled PCR fragments was determined using the ABI
PRISM 310 automated DNA Sequencer (Applied Biosystems,
Foster City, CA) and GeneScan version 3.1.2 software. Samples
with accurate size, assessed by sequencing, were used as controls in
each PCR.
SNPs rs695871 and rs695872 were detected in phase with the
CAG repeat by PCR, with primers SCA2-FP3 and SCA2-RP3
(Fig. 1), as described [Choudhry et al., 2001], followed by sequencing. PCR was carried out with 1 mM of each primer, 260 mM of
dNTPs, 1.25 mM MgCl2, 2.5 U of high fidelity DNA polymerase
(Fermentas), and 10% DMSO, in a final volume of 30 ml. PCR
products were purified from agarose gel, using GFX pCR DNA
and Gel Band Purification kit (GE Healthcare, Buckinghamshire,
UK), and sequencing was performed using a Big Dye Terminator
Cycle Sequencing version 1.1 Ready reaction (Applied Biosystems,
Warrington, UK), in an ABI PRISM 310 automated DNA sequencer. Whenever required, the PCR products were purified and cloned
into a TOPO pcR4 vector, from the TOPO TA cloning kit
(Invitrogen, Carlsbad, CA), according to manufacturer’s
Haplotype Analysis
Haplotype analysis of markers D12S1333 and D12S1672, spanning
a region of 300 kb flanking the repeat—cen-D12S1672-CAG/
CAA repeat-D12S1333-tel (Fig. 1)—was based on segregation
analysis. When the allelic phase could not be determined by
segregation analysis, PHASE 2.1 software (www.stat.washington.
edu/stephens/software.html) was used; based on homozygosity,
and taking into account the known allelic phases introduced, the
probability of all possible haplotype combinations was calculated
for each individual.
Average gene diversity over D12S1333 and D12S1672 loci, that is,
the probability that two randomly chosen haplotypes are different
in the sample, was estimated for our Portuguese and Brazilian SCA2
populations, as well as for others from the literature. Analysis by
Arlequin version 3.11 [Excoffier et al., 2005].
Interruption Pattern of Indeterminate and
Expanded Alleles
Previous studies have reported CAA interruptions in normal alleles
[Choudhry et al., 2001]. In this study, repeat analysis showed CAA
interruptions also in indeterminate penetrance and fully expanded
ATXN2 alleles (Table I). All six indeterminate alleles, with 31–32
repeats, had an interrupted configuration: five showed a CAA
interruption proximal to the 30 -end and shared the C–C SNPbased haplotype with expanded alleles, whereas a 32 CAG/CAA
allele had three interruptions, (CAG)8CAA(CAG)9CAA(CAG)4
CAA(CAG)8, and was associated to the G–T haplotype. The configuration of indeterminate alleles with the C–C haplotype and
expanded alleles with interruptions was similar: (CAG)22–34CAA
(CAG)8,9. Interrupted alleles with 33–44 repeats were previously
reported in one family with parkinsonism [Socal et al., 2009]. In
this study, these alleles (33–44) showed one CAA interruption at
the 30 -end (Table I); each patient from this family had an expanded
allele and also an interrupted 33 repeat allele; from the analysis
of intragenic SNPs and flanking microsatellites (Table II, family
BR2), all these 33–44 alleles showed the same extended haplotype
(10-C–C-5). This indicates that they had the same origin and
FIG. 1. Scheme of the relevant portion of exon 1 of ATXN2. The CAG repeat with the poly(P) and its flanking region is represented, showing the location
of intragenic SNPs (rs695871 and rs695872) and microsatellite markers (D12S1333 and D12S1672) used for the haplotype reconstruction.
TABLE I. Sequence Configuration of ATXN2 Alleles
Repeat length
Interrupted GT alleles
Interrupted CC alleles
Pure CC alleles
Number of chromosomes
Sequence configuration
TABLE II. Haplotype Analysis of SCA2 Expanded Alleles
D12S1333 allele
SNP haplotype
D12S1672 allele
D12S1333: alleles 3 ¼ 225 bp, 4 ¼ 227 bp, 7 ¼ 233 bp, 8 ¼ 235 bp, 9 ¼ 237 bp, 10 ¼ 239 bp, 13 ¼ 245 bp; D12S1672: alleles 5 ¼ 279 bp, 7 ¼ 283 bp, 8 ¼ 285 bp, 9 ¼ 287 bp.aProbabilities for PHASE
haplotypes in parentheses; Brazilian family BR2 showed an interrupted repeat configuration, whereas all the remaining had pure repeats; family BR2 had parkinsonism.
resulted from repeat instability. Two patients in a different family
had a pure tract of 38 CAGs, followed by (CCG)3CCC, instead of the
most commonly observed (CCG)2CCC sequence.
Extended Haplotypes in SCA2 Families
The analysis of SNPs together with STR (D12S1333 and D12S1672)
markers in SCA2 families of Portuguese, Brazilian, Indian, and
Italian origin showed a conserved C–C haplotype, but a great
diversity within and among populations on what concerns more
flanking and unstable polymorphisms (Table II). The Portuguese
families showed two STR haplotypes more frequently associated to
the expansion, 10-Exp-5 and 3-Exp-7, but three other SCA2
haplotypes were observed: 7-Exp-7, 9-Exp-7, and 4-Exp-7. Among
Brazilians, there was one major haplotype, 10-Exp-5, in four
families, followed by the 8-Exp-5 in two families, and 3-Exp-9 in
only one. In the two Indian families, we observed two SCA2
haplotypes: 4-Exp-8 and 3-Exp-8. The haplotype 4-Exp-7 was
shared by the Italian family.
The extended haplotype in alleles with 33, 34, and 44 interrupted
repeats was 10-C–C-Exp-5 (Table II, family BR2), shared by other
five families with pure repeat tracts (Table II). This haplotype was
associated to the disease expansion in a total of six families (four
Brazilian and two Portuguese).
To gain insight into the mutational origin and instability associated
with the ATXN2, we assessed repeat tract configuration and flanking haplotypes of normal and expanded alleles. This is the first
haplotype study of intragenic SNPs in families with SCA2 from
different ethnic origins. This study describes the finding of a
common haplotype for expansions with pure repeats or CAA
interruptions. Interrupted alleles with 33, 34, and 44 repeats shared
the same flanking STR haplotype with five other families, segregating pure repeat tracts. This finding indicates that pure and interrupted expanded alleles share a common ancestral origin and that
interrupted alleles below the pathological threshold may be a
population reservoir of mutable alleles prone to expansion.
These findings have strong implications for mutation analysis
and genetic counseling. We found several indeterminate alleles
(31–32 repeats), interrupted by CAA triplets; based on our findings,
these alleles might expand into the pathological range in subsequent
generations. Furthermore, the polymorphic CCG/CCC tract, immediately adjacent to the (CAG)n, should be assessed by sequencing, at least in intermediate size alleles, since it may misestimate the
number of CAG repeats and therefore have implications in the
mutation diagnosis. It is often not clear if these are included in
repeat size estimation.
Poly(P) Role in SCA2 Alleles
In ataxin-2, the polyglutamine (polyQ) tract is described as being
followed by three proline residues, encoded by the (CCG)2CCC
sequence. We found a family with a (CCG)3CCC sequence in an
expanded allele, immediately adjacent to the poly(Q). Four families
have been reported with a polymorphic (CCG)1–2CAG, in the 30 end of the repeat [Mizushima et al., 1999]. Huntingtin also has a
proline repeat adjacent to the poly(Q), polymorphic in size, which
seems to modulate poly(Q) toxicity in yeast and mammalian cells
[Khoshnan et al., 2002; Dehay and Bertolotti, 2006]. As for huntingtin, two possible roles can be proposed to this proline-rich
region in ataxin-2: it may influence (1) protein interactions of
ataxin-2 and/or (2) the conformation of the poly(Q) region
and, consequently, its structure and toxicity [Bhattacharyya
et al., 2006].
Evolution From Normal to Expanded Alleles
The study of the evolution of normal ATXN2 alleles provides
further insight into the mutational process (Fig. 2). The C–C
haplotype has been identified as the ancestral lineage in several non
-human primates [Choudhry et al., 2001]. Regarding the interrupted tract configuration of human’s closest living evolutionary
relatives, the chimpanzees, our results on ethnically diverse normal
human chromosomes from this lineage suggest (1) the loss of the
most proximal 50 interruption in (CAG)8CAA(CAG)4CAA(CAG)8
alleles; if that is the case, the first CAA would have been corrected to
CAG, originating (CAG)13CAA(CAG)8 alleles, a hypothesis supported by our finding of a similar STR background for both alleles;
(2) that interrupted expanded alleles from the C–C lineage have
originated by a multistep process, as 33- and 44-repeat alleles share
the STR-haplotype with 19 and 23 alleles (Fig. 3); (3) on the other
hand, indeterminate alleles 31 and 32 might have a more distant
origin, with the ancient STR haplotype (4-Ind31-7) shared with the
majority of 22 repeats alleles; in this background, a recombination
upstream the CAG repeat tract would explain the new 8-Ind31-7
haplotype, which, followed by the addition of one CAG at 50 and a
stepwise mutation downstream (between the deleterious repeat and
D12S1672) could have given rise to the 8-Ind32-8 haplotype. A
multistep process has been suggested to underlie the evolution of
normal alleles at other SCA locus [Martins et al., 2006]. Alternatively, a stepwise evolution from the most common 4-Nor22-7 up to
the 10-Exp-5 haplotype, as observed in interrupted alleles with 33,
34, and 44 repeats, would also have been possible in a larger time
scale; nevertheless, more difficult to explain based on our results.
In the G-T lineage, the observation of only 22, 27, and 32 alleles—
with the configurations (CAG)8CAA(CAG)4CAA (CAG)8, (CAG)8
CAA(CAG)4CAA(CAG)8, respectively—suggests a replication process in their evolution. Assuming (CAG)8CAA(CAG)4CAA(CAG)8
alleles as the ancestral form (once they are present also in the
ancestral lineage C–C), alleles 27 would have emerged from alleles
22, by the formation of a hairpin with the sequence CAA(CAG)4 on
the nascent strand; alternatively, by unequal crossing-over, the
cassette-like structure could vary to include an additional CAA(CAG)4 or CAA(CAG)8 (followed by slippage of one CAG); in this
FIG. 2. Postulated expansion mechanism for ATXN2 alleles. Ancestral normal C–C alleles, both by removal of interruptions and by 50 tract expansion,
originated the expanded alleles with pure CAG repeats and also interrupted repeat tracts.
FIG. 3. Extended haplotypes in normal and interrupted alleles. A: G–T lineage: 8-G–T-5 was the most frequent (27.3%), followed by 10-G–T-5 (9.1%);
alleles with 27 repeats carried the G–T haplotype and different flanking STRs. B: C–C lineage: 4-C–C-7 was the most common haplotype (7.8%).
case, however, the less interrupted homologous chromosomes,
arisen by the process, would have been lost.
European Ancestry of the SCA2 Expansions
To identify the mutational origin of SCA2, we studied haplotypes in
families of Portuguese, Brazilian, Indian, and Italian origin. The
C–C haplotype, previously described only in families of Indian
origin [Choudhry et al., 2001], was shared by all these families of
several origins. This suggests (1) a common ancestry for the SCA2
patients, since in the normal population C–C had a frequency of
only 32% (vs. 68% of G–T haplotypes); alternatively, it could reflect
(2) the presence of multiple founders on a predisposing SNP
background. On the other hand, the analysis of STRs, did not
disclose a shared extended haplotype in the ethnically diverse
pedigrees, showing instead different degrees of variability.
A higher diversity was observed in the SCA2 Portuguese families
(average diversity over loci: 0.69 0.55), when compared to the ones
from Brazil (0.48 0.42), India (0.29 0.29 [Pang et al., 1999] or
0.32 0.29 [Choudhry et al., 2001]), or Japan (0.40 0.37
[Mizushima et al., 1999]). A STR haplotype study, including SCA2
families from several ethnic backgrounds, showed different founders
in Europe, whereas a conserved D12S1333–D12S1672 haplotype was
found in three French West Indian families; in addition, diversity
among five North African families led the authors to hypothesize the
existence of independent ancestral mutations [Didierjean et al.,
1999]. The sharing of a SNP-based haplotype by ethnically different
SCA2 families do not support this hypothesis, however, it would be
interesting to analyze the SNP background in these pedigrees as well
as to extend the STR analysis to other North African families.
Overall, the higher diversity in European families with the same
SNP core haplotype suggests an European origin for the ancestral
expansion. In agreement with an European origin of SCA2 is the fact
that the Indian families previously described shared similar flanking
haplotypes; the authors proposed a founder effect in this population [Pang et al., 1999; Choudhry et al., 2001]. The lower genetic
variation in India, together with the presence of the same haplotype
among the (more diverse) European families, suggest that the SCA2
mutation was introduced by Europeans into India. Although lower
than in the Portuguese, the still considerable high variability
observed in Brazilian families (from Rio Grande do Sul) may be
related to their European origins and could reflect multiple introductions of SCA2 in Brazil. One possibility would be its introduction from Italy, where the relative frequency of SCA2 is high
(24–47%) [Filla et al., 2000; Brusco et al., 2004], as in this region of
southern Brazil there is a strong influence of Italian settlements.
In conclusion, we found a shared ancestral ATXN2 SNP-based
haplotype in pure and CAA interrupted alleles in SCA2, with strong
implications for diagnosis, as well as for genetic counseling, as
alleles with interrupted repeat tracts with fewer than 32 triplets may
be a reservoir of alleles prone to expansion in subsequent generations, leading to full disease penetrance.
We would like to thank Victor Mendes for technical assistance. This
work was supported by research grants POCI/SAU-MMO/56387/
2004 and PIC/IC/82897/2007, FCT (Fundaç~ao para a Ci^encia e
Tecnologia) and co-funded by FEDER. S.M. and I.A. are recipients
of scholarships SFRH/BPD/29225/2006 and SFRH/BPD/27781/
2006 (from FCT). The experiments performed comply with the
current laws of Portugal.
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repeat, ataxia, spinocerebellar, common, origin, typed, interrupt, pure, sca2, expansion
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