Human Molecular Genetics 2004 13(Review Issue 2):R235-R243; doi:10.1093/hmg/ddh251
Human Molecular Genetics, Vol. 13, Review Issue 2 © Oxford University Press 2004; all rights reserved
Polyalanine expansions in human
Jeanne Amiel*,
Delphine Trochet,
Mathieu Clément-Ziza,
Arnold Munnich and
Stanislas Lyonnet
Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France
Received June 28, 2004; Revised July 15, 2004; Accepted July 23, 2004
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ABSTRACT
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Beside the well-known polyglutamine expansions involved in several
neurodegenerative disorders, convergent recent findings pointed
to the expansion of polyalanine stretches as a disease mechanism
in congenital malformations, skeletal dysplasia and nervous
system anomalies. Polyalanine stretches have been predicted
in roughly 500 human proteins among which nine have been ascribed
to disease phenotype by expansion of polyalanines. The function
of polyalanine stretches is largely unknown. This paper aims
to review the rapidly growing evidences for a disease-causing
mechanism common to expansion of homopolymeric tracts whatever
the amino acid involved is.
The identification of a new type of mutation, by expansion of CAG trinucleotide repeats coding for polyglutamines in neurodegenerative disorders in human, inspired much enthusiasm in the 1990s. Polymerase slippage has long been assumed to be the disease-causing mechanism. Therefore, imperfect trinucleotide repeats have been discounted as candidate loci for such mutations (reviewed in 1). Some years later, however, imperfect nucleotide repeat expansions encoding alanines were shown to lead to diseases in human according to a different mechanism, namely unequal allelic homologous recombination during meiosis and/or mitosis. The scope of this paper is to review a rapidly growing area concerning this new type of mutation.
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HOMOPOLYMERIC STRETCHES OF ALANINE
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It has been known for long that homopolymeric tracts of amino
acids are extremely abundant in eukaryotic proteins (
2). In
humans 20% of proteins contain at least one (
3). In decreasing
order, the most frequent is glutamic acid, proline, alanine,
serine, leucine, glycine and glutamine (
4). Alanine (A) is a
hydrophobic, non-polar amino acid. Polyalanines have been found
in 494 human proteins (
5). Under physiological conditions
in vitro, alanine stretches form ß sheets that are extremely
resistant to chemical denaturation and enzymatic degradation
(
6). Above a threshold of 19 alanines, the polypeptide aggregates
and forms intracellular inclusions, leading to cell death (
7,
8).
Interestingly, alanine stretches do not exceed 20 alanines in
human and are relatively short homopolymeric repeats when compared
with polyglutamine (poly Q).
Alanine tracts are coded by imperfect trinucleotide repeats (GCN), among which GCG is significantly over-represented in the polyalanine coding sequence (5). It is stable during both meiosis and mitosis (7). However, polymorphisms in length are frequent involving more than 30% of tracts longer than seven alanines and correlating with the length of both the overall tract and the number of a single codon in a row (5). Thanks to the growing genome sequence data available in several species, recent in silico studies concerning homopolymeric tracts have provided valuable information. First of all, polyalanines are frequent in eukaryotic cells, and preferentially found in transcription factors (TFs; 36% of proteins withpolyalanine stretches in humans) (3,5). Comparative proteic sequence data showed that alanine tracts are: (i) longer in eukaryotic cells than in prokaryotic cells, where no tracts longer than nine alanines are found; (ii) poorly conserved among vertebrates and longer in mammals than in other vertebrates; and (iii) of recent and independent appearance in paralogous genes. This last finding is a strong argument for the hypothesis of convergent molecular evolution (5,8) although the functional role(s) of polyalanine stretches remains unknown as well as the nature of the negative selective pressure involved. Indeed, alanine tracts lie outside of other known functional domains in their proteins. However, alanine repeats (as L, P and Q amino acid repeats) do locate preferentially at the N-terminal (4). It is unlikely that they are simply tolerated, non-essential insertions considering their phylogenic evolution and the clear-cut threshold observed in human diseases resulting from expansions of poly A. They have been regarded as flexible spacer elements located between functional domains of the protein and therefore essential to protein conformation, protein–protein interactions and/or DNA binding (3,9). However, although preferentially located in the N-terminal end of proteins when present, their position can be highly variable even within a family of proteins such as the Hox TFs, for example (5).
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EXPANSION OF ALANINE STRETCHES AND HUMAN DISEASE
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An alanine expansion was first identified as the disease-causing
mechanism in synpolydactyly syndrome (SPD) (
10). Since then,
similar mutations have been described in eight additional autosomal
dominant or X-linked disorders responsible, in most of the cases,
for congenital malformations and/or mental retardation (Table
1). Skeletal malformations (SPD, HFGS, CCD) and abnormalities
of the nervous system (HPE, XLAG, XLMR+GH, CCHS) are indeed
over-represented (7/9). Recent general or focused reviews detail
the clinical presentations of each disease (
49–
52). All
but one gene involved encodes a TF (Fig.
1). The exception
concerns the oculo-pharyngeal myotonic dystrophy syndrome (OPMD),
an atypical case on several accounts. Indeed, OPMD is a late-onset,
progressive disease resulting from, and only from, in-frame
duplications leading to polyalanine expansions ranging from
+2 to +7 alanines in the PABPN1 protein (involved in mRNA polyadenylation)
(
7). The size of the alanine expansion leading to a disease
phenotype is the smallest ever described (Table
1). Moreover,
the +1 alanine expansion, found in 2% of the French Canadian
population (
7,
39) may act either as a trans modifier allele
of a larger expansion in severe OPMD cases, or as a disease-causing
allele responsible for a milder form of the disease in homozygous
patients (
7). Although a causal relationship remains to be proven,
it may be worth mentioning that an expansion of 10 alanines
in the 15 alanines tract of the TBX1 protein has been identified
in a patient with conotroncal cardiac defect (
53).
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Figure 1. Schematic structure of proteins involved in polyalanine expansions in humans. Functional domains (gray boxes), polyalanine tracts (red boxes) and other homopolymeric tracts (black boxes, Q, glutamine; H, histidine; G, glycine; P, proline) are indicated. Polyalanine stretches prone to expansion are shown (blue triangles). The size of each protein is indicated (N amino acids). Additional data are found in Table 1. HD, homeodomain; ZNF, zinc-finger; PL-HD, paired-like homeodomain; HMG, high mobility group; ARS, aristaless; RNA-REC, RNA recognition; FKD, forkload.
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GENOTYPE/PHENOTYPE CORRELATIONS IN HUMAN DISEASES RESULTING FROM POLYALANINE EXPANSIONS
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Does the severity of the phenotype vary according to the length
of the alanine tract? Does it vary between patients harboring
a polyalanine expansion when compared with other types of mutations
within the same gene? Positive correlation between the size
of the expansion and the severity of the phenotype is convincing
for the HOXD13 expansions in SPD (
9). Intrafamilial variation
in SPD phenotype is most marked in families with the smallest
expansions (
9). Moreover, SPD has a semi-dominant mode of inheritance
since patients harboring a homozygous duplication (leading to
a +7 or a +9 alanines expansion of the HOXD13 protein) have
a more severe phenotype when compared with heterozygous patients
for the same mutation (
10,
11,
54) suggesting a dose effect of
the mutant protein. Interestingly, hypospadias is observed only
in the SPD patients harboring the longest polyalanine expansion
[+14 alanines (
9)], and incomplete penetrance has been observed
in carriers of heterozygous in-frame duplications leading to
alanine expansions in HOXD13 [+7 and +10 alanines (
10)] and
in HOXA13 [+ 6 alanines (
22)].
Conversely, such correlations are unclear for heterozygous PABPN1 expansions in OPMD (39,40,42) or PHOX2B in CCHS. In the latter case, it has been proposed that the longer the alanine expansion of the PHOX2B protein, the more severe the ventilatory phenotype and the broader thespectrum of autonomic dysfunction in patients (35,36). Indeed, patients with a central hypoventilation syndrome of late-onset (6 months to 12 years in our series of patients) harbor the smallest expansion of the PHOX2B protein if any (+5 alanines), whereas patients with Haddad syndrome (CCHS+Hirschsprung disease) mostly harbor expansions of at least six alanines (33–36). However, one cannot accurately predict the phenotype from the genotype, since the +7 alanines mutation is the most frequent expansion among both the isolated CCHS and the associated to Hirschsprung disease groups of patients (unpublished data). Finally, the question of correlations cannot be raised when an alanine expansion has been reported only once, as is the case for the SOX3 gene, or when all expansions reported have been similar in length (ZIC2 protein, Table 1).
Whenever different types of mutation within the same gene are reported as disease-causing, polyalanine expansions lie at the milder end of the phenotypic spectrum. Such is the case for ARX (32), RUNX2 (22), HOXA13 (16,18,20), FOXL2 (44,45) and PHOX2B. It is worth noting that patients harboring polyalanine expansions do not present features seen in patients with other types of mutations such as ovarian failure in BPEIS, (44,45) brain malformations in XL-MR linked to the ARX gene (32) or neuroblastoma in CCHS (unpublished data).
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DISEASE-CAUSING MECHANISM OF ALANINE EXPANSIONS
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Although it may be inappropriate to consider a common disease-causing
mechanism for alanine expansions, a general discussion may be
proposed (Table
2). When studied, the predicted expanded proteins
have been shown to be present and stable (
7,
52). There are several
arguments against straightforward loss-of-function as the disease-causing
mechanism in disorders resulting from polyalanine expansions.
Indeed, at a single locus, the phenotypes observed are correlated
with the size of the expansion. In addition, the disease is
milder in a polyalanine type of mutation when compared with
other mutations at the same locus highly likely to result in
a plain loss of function (such as deletion encompassing the
gene, missense or truncating mutations within the homeodomain
of the protein). This holds true both in humans (
14,
17,
44,
55)
and mice (
56,
57). Regarding X-linked genes with polyalanine
expansions (
SOX3 and
ARX), the observation of unaffected female
carriers suggests that a gain-of-function of alanine expansions
is unlikely (
30). However, X-inactivation pattern in female
carriers is not known. A dominant negative effect on the wild-type
protein and/or other proteic partners remains a possibility
as shown for HOXD13 expansions in SPD (reviewed in
52).
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MUTATIONAL MECHANISM LEADING TO ALANINE EXPANSIONS
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Warren first suggested that an unequal allelic homologous recombination
was the most likely mechanism for alanine expansions in the
HOXD13 protein (
1). Several lines of evidence support this hypothesis,
namely: (i) almost all variant alleles appear as in-frame duplications
within the nucleotidic sequence encoding the alanine stretch
and can therefore be ascribed to this mechanism; (ii) expanded
alleles are stable mitotically and meiotically over generations
as shown in SPD, HGS, CCHS and OPMD pedigrees (the only exception
being a further expansion of one trinucleotide repeat in the
PABPN1 gene); and (iii) contractions (the mirror image of expansions
during the recombination event) are observed as polymorphisms
in several genes for which expansions lead to human diseases
(
PHOX2B,
ARX,
RUNX2). This mechanism is equally likely in GC-rich
homopolymeric tracts encoded byimperfect codons since the majority
of non-conserved homopolymeric stretches between human and rodents
are the consequence of either expansions or deletions (
58).
PHOX2B is thus far the best gene to analyse how in-frame duplications leading to alanine expansions occur. Indeed, due to poor reproductive fitness, the vast majority of cases are sporadic and de novo in-frame duplications have been reported in more than 100 unrelated CCHS patients world-wide (33–36). As expected, a PHOX2B polyalanine expansion of a given size can be the result of several recombination events as shown in Figure 2 for the three prevalent expansions (+5, +6 and +7 alanines). Intriguingly, for each of the expansion sizes some recombination events are significantly over-represented, whereas some are not observed (Fig. 2). It is worth noting that the most common expansion (+7 alanines) results from an unequal allelic recombination event involving the fewer nucleotide mismatches. It is, thus, tempting to postulate a causal relationship.
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Figure 2. Recombination events observed at the PHOX2B locus in CCHS patients. Recombination events are quoted by all possible crosses. The most frequent (over 60%) recombination event is in bold red, whereas recombination events in black or blue have been observed either once or two to three times, respectively.
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Polymorphisms in the length of the alanine tract have been described
in four genes whose polyalanine expansions mutation results
in human diseases namely the
PHOX2B,
RUNX2,
ARX and
PABPN1 genes
(Table
1). This raises the question of whether nucleotidic variation
would predispose to polyalanine expansion mutation. At least
for the PHOX2B protein, nucleotidic sequence encoding polyalanine
contractions are not prone to expansions during transmission.
Indeed, their frequency is not greater in unaffected parents
of CCHS cases than in a control population (one contracted allele/240
parental alleles versus two contracted alleles/250 control alleles,
respectively, unpublished data). Interestingly, nucleotidic
variations of the third nucleotide of codons encoding alanine
stretches have been reported only for the
HOXD13 (A>G in
the 12th trinucleotide repeat) (
9) and
PHOX2B genes (A>C
in the 14th trinucleotide repeat). One can speculate that selection
may occur against hetero-zygotes if prone to allelic unequal
crossing-over during meiosis (species limited selective pressure).
Interestingly, complex duplication events have been described
in
FOXL2,
HOXD13 and
PHOX2B genes (
16,
32) (Fig.
2) as if
hetero-
zygosity would favor hairpins formations in the genomic
sequence.
Finally, it is worth noting that somatic mosaicism for an alanine expansion in ZIC2 and PHOX2B has been observed in several unaffected parents of probands (27,35,36 and unpublished data), illustrating presumably rare mitotic recombination events.
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WHAT CAN A POLYALANINE TRACT DO?
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Lanz
et al. showed that an artificial alanine tract (replacing
a glutamine tract by an out of frame mutation) in the rat glucocorticoid
receptor (GR) can inactivate transcription. Such an effect could
be observed whatever the polyalanine tract position is in the
protein, despite a length increasing threshold from the N-Ter
to the C-Ter locations (
59). Interestingly, transcriptional
activation is tightly correlated to the number of repeats of
homopolymeric tract (both proline and glutamine tracts) (
60).
Above the physiological range, transcriptional activation drops,
whereas the modified protein remains stable.
Filamentous nuclear inclusions in muscle cells are the hallmark of OPMD. Their cytotoxicity, leading to cell death, may be the consequence of poly(A)RNA sequestration (61,62). Interestingly, when searched for, cytoplasmic aggregates have been observed in several polyalanine diseases such as HFGS, SPD, XL-MR (SOX3 gene) and CCD (62). This finding implicates a change in localization of the mutant protein. Concerning Hoxd13, the rate of cytoplasmic aggregation correlates with the length of the repeat (63). Moreover, as demonstrated in polyglutamine diseases (reviewed in 64), reducing polyalanine aggregation alleviates toxicity. These data cope well with the observation of alanine tracts of more than 19 alanines alone being sufficient to form aggregates (both time-dependent and repeat-length-dependent) in COS-7 cells and cause cell death (65). Accordingly, the longest alanine tract observed in mammals is of 20 amino acids (PHOX2B) (5). Moreover, cell toxicity due to long alanine tracts could extend beyond the scope of trinucleotide repeats encoding alanines. Indeed, GCA repeats may be translated in alanine (GCA), glutamine (CAG) or serine (AGC) codons according to the three possible reading frames. At least in Machado–Joseph disease, large CAG repeats at the MJD-1 locus are prone to frameshifts that could be transcriptional, translational or both. Those frameshifts result in hybrid proteins containing polyglutamine/polyalanine tract that aggregate to form intranuclear inclusions both in vitro and in vivo (66). Along these lines, it is worth mentioning that the expanded CAG/CTG repeats in Huntington disease-like 2 is located in an alternatively spliced exon of the JPH3 gene. One alternate transcript identified in normal brain encodes an alanine tract according to the open reading frame, and affected individuals present intranuclear inclusions of variable extent in the brain (67–69). Therefore, both polyglutamine and polyalanine expansions could lead to protein aggregation due to an alanine stretch rising above a threshold as a slow process in the former case (expected low frequency of frameshifts), and a faster one in the later case (already in-frame alanine coding sequence) and an intermediate one in OPMD where the shortest disease causing alanine tract is of 12 repeats.
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SHOULD SEQUENCES FLANKING ALANINE TRACTS BE CONSIDERED?
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Interestingly, when focusing on the biochemical properties of
amino acids composing homopolymeric stretches, the more hydrophobic
the amino acid (Leu>Ala>Ser>Gln), the shorter the length
of the stretches observed in proteins and the shorter the threshold
in human disease (at least for alanine and glutamine tracts)
(
59,
70). Therefore, not only the length of the homopolymeric
stretch but also the biochemical properties of amino acids flanking
the homopolymeric stretches might be considered. This was proposed
for the rat GR where the threshold in the number of alanines
necessary to inactivate the GR is lowered when the stretch is
flanked by hydrophobic amino acids (
59). If such is the case,
hydrophobic stretches could be lengthened by both unequal allelic
homologous recombination (within the homopolymeric tract) and
nucleotidic variation (outside of it). Among proteins bearing
alanine expansions in human diseases, both the alanine tract
and the flanking amino acids are conserved in human, mouse and
rat orthologs (whenever data are available), even though the
alanine stretches lie outside of known functional domains of
the proteins.
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CAN POLYALANINE CONTRACTIONS BE DISEASE-CAUSING?
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So far, polyalanine contractions have not been involved with
certainty in human diseases. This, however, has been suggested
for the thyroid TF-2 (TTF-2) and the human achaete-scute homolog-1
(HASH-1) genes in thyroid dysgenesis and CCHS, respectively
(
71,
72). Considering that many proteins with polyalanine stretches
interact with each other (
5) polyalanine contractions in one
protein may well modify the transcriptional activity of a proteic
complex in both space- and time-dependant ways, whereas
in vitro transcriptional activity of the contract protein remains within
the range of the wild-type protein (
37,
71,
72). Further functional
characterization is needed before the effect of polyalanine
contractions is established.
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MOUSE MODELS
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Yet, only one natural mouse model with an alanine expansion
has been described; spdh mice mutant for which the Hoxd13 protein
harbors a +7 alanines expansion, as the shorter hitherto observed
in SPD in human (
57). Only mice homozygous for the mutation
show a limb phenotype very similar to the one observed in patients
with SPD, whereas heterozygous mice show very mild limb anomalies.
This observation suggests a discrepancy in dose effect among
species. It could also be regarded as a further argument for
homopolymeric tracts acting as subtle transcriptional activity
modulators. Interestingly, the second amino acid C terminal
to the alanine tract is not conserved among human, mouse and
rat orthologs. Accumulating data on natural or targeted Hoxd13
and Hoxa13 mutants (Hd, Hoxa13 del, Hoxd13 del, Hoxd11–13
del, double mutants and over expression of Hoxd13) converge
to demonstrate the complexity of the regulation of Hox genes
both within and between species (reviewed in
51,
52,
73). Along
the same lines, two strains of mice heterozygous for a loss-of-function
mutation of Phox2b show a fully penetrant eye phenotype only
rarely observed in CCHS patients (
74). Moreover, mice heterozygous
for the targeted deletion of Phox2b show a moderate and transient
ventilatory phenotype when compared with CCHS patients (
75).
Finally, a patient with an interstitial deletion encompassing
the
PHOX2B gene on chromosome 4p12 presented with Hirschsprung
disease as the only feature in common with patients harboring
any type of
PHOX2B gene mutation (
55) supporting disease-causing
mechanisms other than loss-of-function for CCHS and tumoral
phenotypes to occur.
More recently, transgenic mice expressing a Pabpn1 protein with an expansion of three alanines have been generated (76). Mice show a late-onset myopathy phenotype and,accordingly, pathological studies revealed intranuclear inclusions consisting of mutant Pabpn1 protein and developing gradually with aging.
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OTHER AMINO ACID REPEATS AND DISEASE IN HUMAN
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Polyglutamine expansions have been reviewed elsewhere (
64,
77,
78).
Aspartic acid repeats (GAT or GAC) of at least five codons are
unfrequent in eukaryotic proteins (
4). Both in-frame deletion
of one codon and duplication of two codons within the perfect
five trinucleotidic repeats of the
COMP gene encoding an aspartic
acid stretch (lying in the calmodulin-like domain of the protein)
have been identified in pseudoachondroplasia, whereas a duplication
of one codon was found in a patient with multiple epiphyseal
dysplasia (
79,
80). Both conditions have an autosomal dominant
mode of inheritance. Strikingly, inclusions in the rough endoplasmic
reticulum of chondrocytes and tendon cells are described in
both diseases and contain COMP as well as other proteins of
the extracellular matrix (
80,
81). Finally, although polyleucine
expansions have not been described thus far, polyleucine are
more aggregation-prone than polyglutamine
in vitro (
70). Altogether,
these data further support the view of a disease-causing mechanism
common to homopolymeric tract expansions hitherto identified
in human, namely protein aggregation.
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PERSPECTIVES
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Polyalanine expansion may be a rapidly growing disease-causing
type of mutation in vertebrates as polyalanine stretches are:
(i) frequent among key players in development such as TFs; (ii)
rapidly evolving in eukaryotes; and (iii) encoded by sequences
prone to unequal allelic homologous recombination leading to
either expansions or contractions.
It is tempting to speculate on a disease-causing mechanism common to all polyalanine expansions and, to a greater extent, to any amino acid expansions: protein aggregation that traps both mutant and wild-type proteins as well as other protein partners. This time-dependent and repeat-length-dependent mechanism, with variable threshold according to the amino acid involved, could therefore be regarded as gain-of-function with a dominant negative effect. If such is the case, one can expect that the insertion of a sequence encoding an in-frame hydrophobic polypeptide (alanines or leucines) in any gene might be a simple, inducible and tissue-specific knock-out strategy. This may well represent the model proposed by Herskowitz (82).
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FOOTNOTES
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* To whom correspondence should be addressed at: Département de Génétique, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75743 Paris 15, France. Tel: +33 144495136; Fax: +33 144495150; Email:
amiel{at}necker.fr
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ABSTRACT
HOMOPOLYMERIC STRETCHES OF...