Download Unequal Crossing-over in Unique PABP2 Mutations in Japanese

OBSERVATION
Unequal Crossing-over in Unique PABP2 Mutations
in Japanese Patients
A Possible Cause of Oculopharyngeal Muscular Dystrophy
Mika Nakamoto, MD, PhD; Satoshi Nakano, MD, PhD; Shingo Kawashima, MD, PhD;
Masafumi Ihara, MD; Yo Nishimura, MD; Akiyo Shinde, MD; Akira Kakizuka, MD, PhD
Background: Oculopharyngeal muscular dystrophy
(OPMD) is an adult-onset autosomal dominant muscle
disease with a worldwide distribution. Recent findings
reveal the genetic basis of this disease to be mutations in
the polyA binding–protein 2 (PABP2) gene that involve
short expansions of the GCG trinucleotide repeat encoding a polyalanine tract. The underlying mechanism
causing the triplet-expansion mutation in PABP2 remains to be elucidated, although the DNA slippage model
is thought to be a plausible explanation of that.
Methods and Results: We analyzed PABP2 using poly-
merase chain reaction analysis and DNA sequencing in JapanesepatientswithpathologicallyconfirmedOPMD,andfound
mutated (GCG)6GCA(GCG)3(GCA)3GCG and (GCG)6
(GCA)3(GCG)2(GCA)3GCG alleles instead of the normal
(GCG)6(GCA)3GCG allele. These mutated alleles could be
explained by the insertions or duplications of (GCG)3GCA
and (GCG)2(GCA)3, respectively, but not by the simple ex-
O
From the Fourth Department,
Osaka Bioscience Institute,
Osaka (Drs Nakamoto and
Kakizuka), and the
Departments of Neurology,
Kyoto University Faculty of
Medicine, Kyoto (Drs Nakano,
Kawashima, Ihara, and
Shinde), and Nishikobe Medical
Center, Hyogo (Dr Nishimura),
Japan. Dr Nakamoto is now
with the Department of
Neurology, Emory University
Graduate School of Arts and
Sciences, Atlanta, Ga;
Dr Nakano, the Department
of Neurology, Kansai Medical
University, Osaka, Japan; and
Dr Kakizuka, Laboratory of
Functional Biology, Graduate
School of Biostudies, Kyoto
University.
pansion of GCG repeats. The clinical features of our patients
were compatible with those of other Japanese patients carrying PABP2 that encodes a polyalanine tract of the same
length,butwerenotcompatiblewiththoseofItalianpatients.
Conclusions: The mutated alleles identified in our Japanese patients with OPMD were most likely due to duplications of (GCG)3GCA and (GCG)2(GCA)3 but not simple
expansions of the GCG repeats. Therefore, unequal crossingover of 2 PABP2 alleles, rather than DNA slippage, is probably the causative mechanism of OPMD mutations. All mutations that have been reported in patients with OPMD so
far can be explained with the mechanism of unequal crossing-over. On the other hand, comparison of the clinical features of our patients with those of other patients in previous reports suggests that specific clinical features cannot
be attributed to the length of the polyalanine tract per se.
Arch Neurol. 2002;59:474-477
CULOPHARYNGEAL muscu-
lar dystrophy (OPMD) is
a distinct clinicopathologic category of lateonset autosomal dominant muscle disorders. The disease is
characterized by progressive dysphagia,
ptosis, and limb muscle weakness.1 The hallmark of OPMD is the accumulation of
8.5-nm tubulofilamentous inclusions within
the nuclei of skeletal muscle fibers.2
Genetically,short(GCG)8-13 expansions
of a (GCG)6 repeat located in exon 1 of the
polyA binding–protein 2 (PABP2) gene were
determined to be the genetic basis of this disease in 1998.3 This gene encodes PABP2, a
nuclear protein known to bind to polyA tails
of messenger RNAs and to control their
length.4,5 In the normal allele, (GCG)6 is followed by a (GCA)3GCG nucleotide sequence. Since the GCG and GCA codons are
translated into alanine residues, the normal sequence is translated into a stretch of
10 alanine residues. In the diseased allele,
(GCG)6 is expanded to (GCG)8-13, resulting in an elongation of the length of the polyalanine tract to 12 to 17 tandem repeats of
(REPRINTED) ARCH NEUROL / VOL 59, MAR 2002
474
alanine in the PABP2 protein. It has been
suggested that these polyalanine expansions
induce aggregation of the PABP2 protein
into insoluble inclusions. Recent studies
have shown that the 8.5-nm tubulofilamentous nuclear inclusions found in OPMD are
composed of the PABP2 protein.6 The disease is thought to be a consequence of the
toxic effects of the aggregates or of the dysfunction of the protein.6
Our report serves 2 purposes. First, the
underlying mechanism causing the tripletexpansion mutation in PABP2 remains to be
elucidated,althoughtheDNAslippagemodel
is thought to be a plausible explanation. We
analyzed PABP2 in patients from 2 unrelated
Japanese families with OPMD who had
OPMD-specific nuclear inclusions in their
skeletal muscle fibers, and found 2 unique
mutations. Our findings show that the arrangements of the nucleotide sequences detected in our patients indicated that unequal
crossing-over could be a mechanism causing the triplet-repeat expansion in OPMD.
Second, in many other triplet-repeat
disorders, a gene-dosage effect and an inverse relationship between the age of on-
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SUBJECTS AND METHODS
REPORT OF CASES
Thefirstpatient(patientA)wasa65-year-oldmanborninHyogo
Prefecture, Japan. At 55 years of age, a swallowing disturbance
developed. At 60 years of age, he noticed ptosis on both sides,
which gradually worsened. Results of an examination showed
moderate ptosis and mild weakness of the facial and pharyngeal muscles. Extraocular muscles showed no weakness. He
exhibitedmoderatesymmetricalweaknessoftheproximallower
limbmuscles.Resultsoflaboratoryexaminationshoweda6-fold
increase in serum creatine kinase (CK) level (843 U/L; reference value, ⬍141 U/L). His father had had dysphagia and dysarthria since the sixth decade of life. A sister of patient A had
had dysphagia since her sixth decade of life, whereas a brother
had no neuromuscular symptoms.
The second patient (patient B) was a 69-year-old woman
born in Shiga Prefecture, Japan. She had no neuromuscular
symptoms until 61 years of age, when she noticed ptosis on
both sides. The symptoms progressed gradually, and she underwent an operation for it at 65 years of age. At 66 years of
age, easy fatigability on walking, swallowing difficulty, and
speech disturbance developed. Results of an examination disclosed ptosis that completely covered the pupils. Medium
grade of ophthalmoparesis was noted in all directions. Eye
and mouth closures were moderately impaired. She had moderate symmetrical muscle weakness of the proximal limb and
neck muscles. Her serum CK level was 300 U/L. She was separated from her parents in early childhood, which hindered
confirmation of parental symptoms. She had a sister with ptosis and a child without neuromuscular symptoms.
In patients A and B, results of muscle biopsy revealed
the occasional occurrence of muscle fibers containing
rimmed vacuoles. Results of electron microscopic studies
showed intranuclear tubulofilamentous inclusions with a
diameter of 8.5 nm, which is a characteristic of OPMD.
METHODS
We analyzed PABP2 in both index patients and the 2 siblings of patient A after obtaining informed consent.
set as well as clinical severity of the disease and the length
of the pathologically expanded repeat have been reported.7 With regard to a gene-dosage effect in OPMD, studies in the 2 largest clusters (French Canadians and Bukhara
Jews) showed that patients who were homozygous for the
(GCG)9(GCA)3GCG allele exhibited more severe clinical
features than those who were heterozygous for the mutation.3,8 However, it is unclear whether such an inverse relationship exists in OPMD. This uncertainty is partially due
to the 2 largest clusters of OPMD, which are almost homogeneous for the mutation, probably resulting from a
founder effect.3,8,9 We investigated the relationship between genotype and phenotype in our patients.
RESULTS
Sequence analyses disclosed a 12–base pair (bp) elongation in patient A and his affected sister and a 15-bp elongation in patient B (Figure 1) within the (GCG)6(GCA)3
(REPRINTED) ARCH NEUROL / VOL 59, MAR 2002
475
Biopsy specimens of muscle tissue from patients A and
B were stored at −70°C and were then cut into 5- to 10-mg
sections using a razor. The sections of muscle tissue were
incubated in a solution containing 50mM Tris hydrochloride (pH, 8.0), 10mM EDTA, 100mM sodium chloride, 0.5%
sodium dodecyl sulfate, and 1-mg/mL proteinase K (Boehringer Mannheim, Mannheim, Germany) for 5 hours at
50°C. After phenol extraction, genomic DNA was precipitated using 99% ethanol, then dissolved in a solution consisting of 10mM Tris hydrochloride (pH, 7.5) and 0.1mM
EDTA. Peripheral blood samples were obtained from the
2 siblings of patient A and Japanese control subjects. Genomic DNA was extracted from the samples with the use
of a blood kit (QIAamp; QIAGEN, Hilden, Germany) according to the manufacturer’s instructions.
Polymerase chain reaction analysis was performed
in 50-µL volumes containing 100 ng of genomic DNA,
250µM of each dNTP (ie, doxyadenosine triphosphate,
deoxyguanosine triphosphate, deoxycytidine triphosphate, and deoxythymidine triphosphate), 1µM of the
forward 5⬘-CGCAGTGCCCCGCCTTAGAGGTG-3⬘ and
backward 5⬘-ACAAGATGGCGCCGCCGCCCCGGC-3⬘
primers, 1.25 U of Taq DNA polymerase (TaKaRa LA Taq;
TaKaRa, Kyoto, Japan) and its specific reaction buffer (GC
Buffer II; TaKaRa). After initial denaturation at 95°C for 5
minutes, amplification was performed in 30 cycles consisting of denaturation at 95°C for 18 seconds, annealing at
70°C for 30 seconds, and extension at 74°C for 40 seconds. The final extension proceeded at 74°C for 10 minutes. Products were separated on a 5% nondenaturing
polyacrylamide gel. After electrophoresis, the gels were
stained using ethidium bromide. Allele-specific bands
were excised from the gels, eluted, and subcloned into a
plasmid vector (pGEM-T Easy Vector; Promega, Madison,
Wis). Sequencing of the normal and mutated fragments
was performed bidirectionally using a dideoxy sequencing
kit (Amplicycle; Applied Biosystems, Foster City, Calif)
on at least 6 clones for every allele, for validation. The
sequences obtained were compared with the genomic
sequence of the human PABP2 gene (accession number
AF026029; GenBank, Bethesda, Md; available at: http:
//www.ncbi.nlm.gov/entrez/query).
GCG normal sequence in exon 1 of PABP2. The mutated
sequence detected in patient A and his sister was (GCG)6
GCA(GCG)3(GCA)3GCG, and that in patient B was (GCG)6
(GCA)3(GCG)2(GCA)3GCG. Both sequences could be explained by the insertions or duplications of (GCG)3GCA
and (GCG)2(GCA)3, respectively, into the normal sequence. The normal sequence in PABP2 is translated into
a series of 10 alanine residues. The mutations in our patients increase the number of alanine residues encoded from
10 to 14 in patient A and his sister, and to 15 in patient B.
All of the patients were heterozygous for the mutated and
the normal alleles. The unaffected brother of patient A was
homozygous for the normal allele.
In addition to the duplications, we observed in all
patients and 10 Japanese controls a CG-to-GGGC change
in position 1146, a G deletion in position 1215, a GG insertion in position 1229, and an ATC-to-CAT change in
position 1250 (Figure 2). The latter 2 changes have previously been described in an Italian population.10 All 4
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A
Normal Allele
GCG GCG GCG GCG GCG GCG GCA GCA GCA GCG
Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala
Polymorphic Allele
Normal
GCG GCG GCG GCG GCG GCG GCG GCA GCA GCA GCG
Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala
B
Normal Allele
X
Mutation A
Normal Allele
Mutant Allele
GCG GCG GCG GCG GCG GCG GCG GCG GCG GCG GCG GCA GCA GCA GCG
Mutation B
C
Normal Allele
X
Normal Allele
Figure 1. Mutant sequences found in Japanese patients with
oculopharyngeal muscular dystrophy. Electropherograms of alleles of the
polyA binding–protein 2 gene show normal allele, mutant allele detected in
patient A (mutation A), and that detected in patient B (mutation B). Open
circles represent GCG triplets; filled circles, GCA triplets.
Mutant Allele
GCG GCG GCG GCG GCG GCG GCA GCG GCG GCA GCA GCA GCG
D
Normal Allele
1215
G Deletion
1250
ATC→CAT
X
Normal Allele
1283
1633
Mutant Allele
GCG GCG GCG GCG GCG GCG GCA GCG GCG GCG GCA GCA GCA GCG
Exon 1
1146
CG→GGGC
1229
GG Insertion
Figure 2. Schematic representation of the exon 1 structure of the polyA
binding–protein 2 gene. The horizontal line and the box indicate the
5⬘-untranslated region and the coding region of the exon 1, respectively.
Positions of the 4 putative polymorphisms identified in the Japanese population
are represented by vertical lines in the 5⬘-untranslated region. The filled portion
of the box indicates the location of the sequence depicted in Figure 1; arrows,
the positions of the polymerase chain reaction primers used in this study.
changes are located in the 5⬘-untranslated region of PABP2
and were present in all healthy and affected Japanese subjects studied. This indicates that they may be polymorphisms; the former two are characteristic to date of the
Japanese population and the latter two are shared to date
by the Japanese and Italian populations.10
COMMENT
MECHANISM OF
REPEAT EXPANSIONS IN OPMD
Except for the mutation found in Cajun patients who had
a (GCG)6GCA (GCG)2(GCA)3GCG mutated allele,11 all
of the PABP2 mutations reported so far in patients with
OPMD were expansions of the (GCG)6 repeat. These expansions make a (GCG)8-13(GCA)3GCG allele from the
(GCG)6(GCA)3GCG normal sequence.3 We found 2 novel
mutations, (GCG) 6 GCA(GCG) 3 (GCA) 3 GCG and
(GCG)6(GCA)3(GCG)2(GCA)3GCG, in Japanese patients with OPMD.
The molecular mechanism causing the repeat expansion in PABP2 has not been determined. In general,
the following 2 types of mechanisms leading to the generation of longer DNA sequences have been proposed:
replication- and recombination-associated expansion.12
Repeat expansions that involve the process of DNA replication may originate from slipped mispairing between re(REPRINTED) ARCH NEUROL / VOL 59, MAR 2002
476
E
Normal Allele
X
Normal Allele
Mutant Allele
GCG GCG GCG GCG GCG GCG GCA GCA GCA GCG GCG GCA GCA GCA GCG
Figure 3. Schematic representation of GCG and GCA repeats found in the
polyA binding–protein 2 (PABP2 ) gene. Open circles represent GCG triplets;
filled circles, GCA triplets; Xs, possible points of the DNA crossing-over; and
underlines, duplicated nucleotides. A, Normal and polymorphic alleles of
PABP2 found in healthy individuals consist of alanine-encoding 10- and
11-triplet repeats, respectively. B-E, All of the reported mutant PABP2 alleles
can be generated by unequal crossing-over.
peated sequences, as has been described for the slippage
model.13 It has been shown recently that expanded triplet
repeats are responsible for a number of hereditary neuromuscular diseases.7,14,15 These pathologic repeat expansions
can be explained by the slippage model. However, it has been
proposed that tracts of approximately 25 to 35 perfect trinucleotide repeats are required for instability and expansion via slippage.16 The heterogeneous sequences of the mutated alleles of PABP2 detected in the Cajun patients and
our Japanese patients and the fact that even the longest perfect repeat reported (13 repeats) is less than 25 repeats argue against the slippage model.
Recombination-associated repeat expansion may result from homologous recombination, which occurs in germ
cells during meiosis and sometimes during mitosis.12 The
mutations that we found suggest that the molecular mechanism resulting in generation of longer DNA sequences in
PABP2 is unequal crossing-over (Figure 3), which is a kind
of homologous recombination. The (GCG)6(GCA)3GCG
normal allele was reported to be found in 98% and 99%
of French Canadian and Japanese control chromosomes, respectively, whereas the rest of both populations carried a (GCG) 7 (GCA) 3 GCG polymorphism
(Figure 3A).3,17 Unequal pairing with variable degrees of
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overlap can generate each of the (GCG)8-12(GCA)3GCG
mutant alleles by crossing-over of the 2 (GCG)6(GCA)3
GCG normal alleles (Figure 3B). At most, a (GCG)13
(GCA)3GCG allele can be derived by unequal crossingover of the (GCG)6(GCA)3GCG normal allele and the
(GCG)7(GCA)3GCG polymorphic allele. This mechanism can also explain the (GCG)6GCA(GCG)2(GCA)3
GCG mutation reported in Cajun patients (Figure 3C)11
and the (GCG)6GCA(GCG)3(GCA)3GCG (Figure 3D)
and (GCG)6(GCA)3(GCG)2(GCA)3GCG mutations found
in our patients (Figure 3E). Since the (GCG)8-10(GCA)3
GCG pathologic expansions in PABP2 are reported to be
stable with no variation among family members and between such different tissues as blood and skeletal muscle
in the same individual,10 we suspect that unequal crossingover occurred once at meiosis in an ancestor of each patient with OPMD. Similar expansions of cryptic repeats composed of mixed synonymous codons causing a polyalanine
expansion in the homeobox D13 (HOXD13) protein has
been found to cause synpolydactyly.18 The HOXD13 mutation has been explained by unequal crossing-over.19
GENOTYPE/PHENOTYPE
RELATIONSHIP IN OPMD
The muscle degeneration seen in OPMD may be a consequence of the toxic effects of the aggregates caused by the
expanded polyalanine tracts, or of the altered properties
of the mutated PABP2 protein.6 In both cases, the length
of the polyalanine tract may be a key determinant of the
effect. The (GCG)6(GCA)3GCG sequence in the normal
PABP2 gene is translated into 10 alanine residues in the protein. The mutated alleles in our patients encode 14 and 15
alanine residues instead of 10. In that case, the number of
alanine residues in our patients are equivalent to those reported to be generated by the (GCG)10(GCA)3GCG and
(GCG)11(GCA)3GCG expanded alleles, respectively.
All of our patients were heterozygous for the mutations. To our knowledge, only 1 Japanese family and 2 Italian families heterozygous for the (GCG)10(GCA)3GCG allele and 2 Japanese families heterozygous for the (GCG)11
(GCA)3GCG allele have been described clinically and genetically.10,20,21 According to the reports, dysphagia with
moderately increased CK levels and proximal myopathy
of the lower legs initially developed in the Japanese patients heterozygous for the (GCG)10(GCA)3GCG allele.20
Ptosis first developed in the 2 Japanese families heterozygous for the (GCG)11(GCA)3GCG allele, whereas their CK
levels were generally within normal limits or only mildly
increased.20,21 These clinicogenetic correlations are compatible with those of our patients, especially with respect
to the initial symptoms and CK levels. However, both Italian families heterozygous for the (GCG)10(GCA)3GCG allele presented with ptosis as the first symptom, with later
development of dysphagia and severe weakness of limb
and pelvic girdle muscles.10 Therefore, the specific clinical feature perhaps cannot be attributed to the length of
the polyalanine tract of PABP2 per se. Although these observations argue that the pathologic characteristics of
OPMD may be the result of nucleotide configuration, intrapopulational similarities of phenotype among the Japanese and among the Italian patients are more likely to be
(REPRINTED) ARCH NEUROL / VOL 59, MAR 2002
477
due to the genetic background of each race. Further case
accumulation is needed to clarify the relationship between genotype and phenotype in OPMD.
Accepted for publication August 9, 2001.
Author contributions: Study concept and design, analysis and interpretation of data, and obtained funding (Drs
Nakamoto and Kakizuka); acquisition of data (Drs Nakamoto, Nakano, Kawashima, Ihara, Nishimura, and Shinde);
drafting of the manuscript (Dr Nakamoto); critical revision of the manuscript for important intellectual content
(Drs Nakamoto, Nakano, Kawashima, Ihara, Nishimura,
Shinde, and Kakizuka); and administrative, technical, and
material support and study supervision (Dr Kakizuka).
This work was supported by research fellowships from
the Japan Society for the Promotion of Science for Young
Scientists, Tokyo (Dr Nakamoto), and by CREST, Japan Science and Technology Corporation, Saitama.
We thank Akiko H. Popiel for the proofreading.
Corresponding author and reprints: Akira Kakizuka, MD,
PhD, Laboratory of Functional Biology, Graduate School of
Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku,
Kyoto 606-8501, Japan (e-mail: [email protected]).
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