Human Molecular Genetics, 2000, Vol. 9, No. 15 2321-2328
© 2000 Oxford University Press
Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA
Institute of Histology and Embryology, Faculty of Medicine, University of Lisbon, Avenida Prof. Egas Moniz, 1649-028 Lisbon, Portugal, 1INSERM U523, Institut de Myologie, Hôpital de la Salpêtrière, Paris, France, 2Centre de Reserche du CHUM, Université de Montréal, Canada, 3Centre for Research in Neurosciences, McGill University, Montréal, Canada and 4Institut für Biochemie, Universität Halle, Germany
Received 16 June 2000; Revised and Accepted 4 August 2000.
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ABSTRACT |
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Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. The autosomal dominant form of the disease is caused by short (GCG)8–13 expansions in the PABP2 gene. This gene encodes the poly(A) binding protein 2 (PABP2), an abundant nuclear protein that binds with high affinity to nascent poly(A) tails, stimulating their extension and controlling their length. In this work we report that PABP2 is detected in filamentous nuclear inclusions, which are the pathological hallmark of OPMD. Using both immunoelectron microscopy and fluorescence confocal microscopy, the OPMD-specific nuclear inclusions appeared decorated by anti-PABP2 antibodies. In addition, the inclusions were labeled with antibodies directed against ubiquitin and the subunits of the proteasome and contained a form of PABP2 that was more resistant to salt extraction than the protein dispersed in the nucleoplasm. This suggests that the polyalanine expansions in PABP2 induce a misfolding and aggregation of the protein into insoluble inclusions, similarly to events in neurodegenerative diseases caused by CAG/polyglutamine expansions. No significant differences were observed in the steady-state poly(A) tail length in OPMD and normal myoblasts. However, the nuclear inclusions were shown to sequester poly(A) RNA. This raises the possibility that in OPMD the polyalanine expansions in the PABP2 protein may interfere with the cellular traffic of poly(A) RNA.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease, which usually starts in the late forties. The disease is characterized by progressive eyelid drooping (ptosis), swallowing difficulties (dysphagia) and proximal limb weakness. OPMD was first described in four members of a French-Canadian family (1) and later reports showed that it has a world-wide distribution (2–4). A pathological hallmark of this disease consists of filamentous intranuclear inclusions, which are exclusively detected in muscle fibers (5,6). When viewed with the electron microscope, the OPMD inclusions are composed of filaments, which have a tubular appearance with an outer diameter of 8.5 nm, an inner diameter of 3 nm and a length of
0.25 µm. The filamentous inclusions are seen in several muscle fiber nuclei and their size varies greatly (5,6). OPMD is usually inherited as an autosomal dominant trait with complete penetrance and without sexual preference. The OPMD locus was mapped to chromosome 14q11 (7) and the mutated gene was recently identified as the gene encoding the poly(A) binding protein 2 (PABP2) (8). The dominant OPMD mutation consists of short (GCG)8–13 expansions causing the lengthening of a polyalanine tract located at the N-terminus of the PABP2 protein.
PABP2 is an abundant nuclear protein that binds with high affinity to nascent poly(A) tails. Poly(A) tails are post-transcriptionally added to the 3' ends of all eukaryotic mRNAs, with the single exception of histone messengers (9). In the cytoplasm, poly(A) tails increase the efficiency of translation initiation and help to stabilize the mRNAs (10,11).
The formation of poly(A) tails in the nucleus involves a number of trans-acting protein factors (reviewed in refs 12–15). These include cleavage and polyadenylation specificity factor (CPSF), cleavage stimulation factor (CstF), cleavage factors Im and IIm (CF Im and CF IIm), poly(A) polymerase (PAP) and PABP2. The precursor RNA (pre-mRNA) is first endonucleolytically cleaved at a particular phosphodiester bond and the resulting 3'-OH group then receives 
250 adenylate residues. The polyadenylation reaction is catalyzed by poly(A) polymerase, but this enzyme by itself has a very low and unspecific affinity for RNA. In the 3'-end-processing complex, poly(A) polymerase must interact with CPSF in order to be tethered to the primer. However, poly(A) synthesis in the presence of poly(A) polymerase and CPSF, is slow and inefficient. Processive and efficient polymerization requires an additional factor, PABP2 (16,17). Mammalian cells contain two distinct poly(A) binding proteins, PABP1 and PABP2. Although both proteins shuttle between the nucleus and cytoplasm (18–20), at steady-state PABP1 is localized in the cytoplasm (21) whereas PABP2 is present in the nucleus (20,22). Consistent with its nuclear localization, PABP2 is the mammalian protein that stimulates processive poly(A) addition and controls the size of the tail to 250 nucleotides in length (16,23,24). PABP1, which is the mammalian counterpart of the essential yeast Pab1p (51% identity) (25), is apparently involved in both cytoplasmic mRNA stability (26–30) and translation (31,32).
The present work identifies PABP2 as a component of the characteristic filamentous inclusions present in muscle fiber nuclei from OPMD patients. The PABP2 inclusions are shown to be resistant to salt extraction, to be decorated by antibodies to ubiquitin and the proteasome and to contain poly(A) RNA. These findings suggest that the pathological (GCG)n expansions in the PABP2 gene cause aggregation of the protein into insoluble inclusion bodies which may sequester poly(A) RNA.
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RESULTS |
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Detection of PABP2 in OPMD nuclear inclusions
The subcellular distribution of PABP2 was analyzed in muscle biopsies from three OPMD patients belonging to unrelated families, one patient with inclusion body myositis (IBM) and one normal control. Immunofluorescence reveals that anti-PABP2 antibodies label the nuclei from all muscle cell types (Fig. 1A and B). Within muscle fiber nuclei, which are easily identified by their peripheral location and elongated structure, PABP2 is normally detected throughout the nucleoplasm excluding the nucleolus (Fig. 1C–E), as previously described in cultured cell lines (20,22). However, in OPMD patients, several muscle fiber nuclei contain an inclusion body which is brightly stained by anti-PABP2 antibodies (Fig. 1A, B and F–H, arrows). These inclusions appear round or oval and are of variable size. The intranuclear inclusions are systematically seen as the most intensely labeled structures, indicating that they contain a higher concentration of PABP2 than is normally present in the nucleoplasm. The PABP2 inclusions often occupy an area similar to that of the nucleolus and, similarly to this organelle, they are largely devoid of DNA (Fig. 1G). The PABP2 inclusions are seen exclusively in the nuclei of muscle fibers from OPMD patients. They are not found in the nuclei of satellite cells or any other type of cell present in OPMD biopsies. Moreover, the nuclear inclusions present in muscle from patients with IBM, were not stained by anti-PABP2 antibodies (data not shown).
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Viewed under the electron microscope, the OPMD nuclear inclusions consist of collections of tubular filaments
8.5 nm in external diameter, disposed in tangles or palisades (Fig. 2A). To unambiguously identify the presence of PABP2 in these structures immunoelectron microscopy was performed. Tissue samples from OPMD patients and controls were fixed in formaldehyde, embedded and ultrathin sections were incubated with anti-PABP2 antibodies. Figure 2B depicts a thin section through a deltoid muscle fiber nucleus from an OPMD patient. The gold particles decorate the characteristic aggregates of tubular filaments, which are not membrane-bound and are less electron-dense than the surrounding nucleoplasm. In addition to the filamentous inclusions, which are exclusively observed in OPMD tissue, PABP2 is detected in nucleoplasmic clusters of interchromatin granules both in OPMD and normal muscle samples (data not shown), as previously described in cultured cell lines (22).
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The OPMD nuclear inclusions contain insoluble PABP2 and recruit proteasomes
It is currently accepted that the aggregates seen in several familial degenerative diseases result from aberrant properties of the mutated protein leading to tissue deposition. This prompted us to compare the solubility of normal and mutated PABP2. As pathological aggregates are typically non-dissociable in 1 M KCl (33), cryostast sections of muscle biopsies were treated with 1 M KCl for 5 min before fixation and immunolabeling with anti-PABP2 antibodies. This treatment completely abolishes nucleoplasmic staining, whereas the inclusions remain labeled (Fig. 3). Thus, PABP2 present in the inclusions resists 1 M salt extraction, whereas the protein localized in the nucleoplasm is solubilized.
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Supporting evidence for the view that pathological inclusion bodies are produced by aberrant protein is provided by the detection of ubiquitin and proteasomes in the aggregates formed by polyglutamine-expanded ataxin-1 (34), ataxin-3 (35) and androgen receptors (36). In fact, the ubiquitin–proteasome system is the major intracellular pathway for degradation of damaged or misfolded proteins (reviewed in refs 37–40). Abnormal proteins are specifically recognized, modified by the covalent conjugation of ubiquitin and then degraded by the proteasome, which is composed of a 20S catalytic core and a regulatory 19S cap.
Immunofluorescence shows that ubiquitin is detected in OPMD nuclear inclusions (Fig. 4A), as previously described (41). In addition, the intranuclear inclusions are also found to be immunopositive using antibodies directed against the 20S catalytic subunit of the proteasome (Fig. 4B and C). This suggests that either the filamentous polymers of polyalanine-expanded PABP2 or other proteins present in the inclusions are ubiquitinated and targeted for degradation by the proteasome.
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The OPMD nuclear inclusions sequester poly(A) RNA
Since normal PABP2 binds with high affinity to nascent poly(A) tails and co-localizes in the nucleoplasm with poly(A) RNA (20), we investigated whether the OPMD-specific nuclear inclusions also contain poly(A) RNA. To detect poly(A) RNA, fluorescence in situ hybridization was performed using an oligo(U) probe. In all muscle samples analyzed, this probe labels the cytoplasm and the nucleus, excluding the nucleolus. In addition, some muscle fiber nuclei from OPMD patients contain intensely stained inclusions (Fig. 5A). Double-labeling using the oligo(U) probe and the anti-PABP2 antibodies confirms that OPMD inclusions are highly enriched in both PABP2 and poly(A) RNA (Fig. 5B). As a control, hybridization was performed using a probe complementary to 28S ribosomal RNA. This probe labels the nucleolus, but not the OPMD inclusions (Fig. 5C and D).
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In conclusion, OPMD inclusions are shown to contain a higher concentration of poly(A) RNA than is normally found in the nucleoplasm. This suggests that polyalanine-expanded PABP2 is sequestering poly(A) RNA in the nuclear inclusions.
Poly(A) tail length is normal in OPMD muscle
The cellular function of PABP2 consists in stimulating processive poly(A) addition and controlling the size of the poly(A) tail to 250 nucleotides in length (16,19,23,24). To investigate whether the pathological polyalanine expansions in PABP2 interfere with poly(A) tail formation, we determined the steady-state poly(A) tail length in muscle cells from OPMD patients and normal controls.
Poly(A) mRNA isolated from cultured myoblasts of seven individuals was analyzed by 3'-labeling and RNase digestion (Fig. 6). Complete digestion with RNase A (pyrimidine specific) and RNase T1 (guanosine specific) leaves only the poly(A) tails intact and allows a comparison of the poly(A) tail length distribution of steady-state RNA. An internally labeled control RNA (L3pre) was totally degraded by RNase A and RNase T1 digestion (Fig. 6, compare lanes L3pre ± RNase), whereas, as expected, poly(A) was not affected by RNase treatment [compare lanes poly(A) ± RNAse].
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RNA fragments in samples 1–7 represent the steady-state poly(A) tail length distribution of wild-type control individuals (samples 1–3), three heterozygous cases (samples 4–6) and one homozygous OPMD patient (sample 7) (42). No difference in poly(A) tail length distribution was observed either in the analysis of poly(A) RNA (Fig. 6, lanes 1–7) nor in the case of total RNA samples (data not shown). Thus, polyalanine expansions in PABP2 do not change the steady-state poly(A) tail length distributions.
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DISCUSSION |
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The presence of abnormal protein deposits in human tissues is a relatively common finding in degenerative diseases. For instance, neuronal degeneration in Alzheimer’s disease is preceded by the appearance of intracellular aggregates of neurofibrillary tangles made up of a protein called tau. The tau protein aggregates when it is hyperphosphorylated and recent data suggest that this hyperphosphorylation is caused by a deregulation of Cdk5 (43,44). Another recently described example is a type of familial dementia caused by polymerization of mutant neuroserpin in the brain (33). An additional group of disorders associated with aggregation of abnormal proteins consists of inherited neurodegenerative diseases caused by expansion of CAG/glutamine repeats (reviewed in refs 45,46). In these diseases, the CAG repeat expansion results in an expanded polyglutamine tract in otherwise unrelated proteins. This group of disorders shares with OPMD the presence of intranuclear inclusion bodies. In many cases the abnormal proteins are detected in the inclusions, and formation of the deposits precedes the appearance of symptoms (47–51). Furthermore, the disease-associated proteins precipitate in vitro as insoluble fibers, whereas their counterparts from normal individuals are soluble. Based on these data, a model has been proposed in which polyglutamine expansion confers a toxic gain-of-function property on the protein (46). Although this novel property likely involves an increased tendency of the mutant protein to misfold and aggregate, a direct cause-and-effect relation between nuclear inclusions and the disease mechanisms remains to be demonstrated (52–55).
The recent identification of (GCG)n expansions in the PABP2 gene as the cause of OPMD makes this disorder a novel type of triplet-repeat disease. This raises the question of whether polyalanine expansions in PABP2 are responsible for the filamentous inclusions present in the nuclei of OPMD muscle fibers (4,8). The data described here provide three lines of evidence supporting this view. First, the OPMD-specific nuclear inclusions contain PABP2. Second, the PABP2 protein present in the inclusions is more resistant to 1 M salt extraction than the protein localized outside the inclusions. Third, the nuclear inclusions are labeled by anti-ubiquitin and anti-proteasome antibodies, suggesting that these deposits contain aberrant proteins recognized and targeted to the ubiquitin–proteasome degradation pathway (56).
Consistent with the view that OPMD inclusions represent polymers of polyalanine-expanded PABP2, atomic models show that poly-L-alanine chains, as either ß-strands or 
-helices, would adhere to each other through non-polar interactions between their methyl side chains and are therefore predicted to form aggregates (46). Accordingly, polyalanine oligomers were found to be extremely resistant to chemical denaturation and enzymatic degradation (57,58). Furthermore, green fluorescent protein constructs with a 19–37 polyalanine domain, were found to cause intracellular inclusions and cause cellular death (59).
Having established that OPMD nuclear inclusions are most likely formed by polyalanine-expanded PABP2, the key question is whether these filamentous aggregates are responsible for the disease. In the case of polyglutamine expansions, expression of apparently any protein with an expanded glutamine repeat produces nuclear inclusions and causes neuronal cell death (60). Yet, certain types of tissue with nuclear inclusions are not affected, suggesting that the toxicity of the aggregates is cell type specific (61). One possibility is that the polyglutamine aggregates are pathogenic due to a sequestering of other glutamine-containing cellular proteins (62). Alternatively, it has been proposed that the inclusions are not toxic but rather protect neurons from cell death (55).
Taking into account the above data, the muscle degeneration observed in OPMD patients may be a consequence of either toxicity of the aggregates caused by the polyalanine chains, or the altered properties of the mutated PABP2 protein. Particularly striking are the facts that PABP2 binds with high affinity to nascent poly(A) tails of mRNA and poly(A) RNA is detected in the OPMD inclusions at higher concentration than in the rest of the cell (Fig. 5). No difference in poly(A) tail length distribution was observed in cultured myoblasts from a homozygous OPMD patient (Fig. 6), suggesting that polyalanine expansions do not affect the polyadenylation function of PABP2. However, recent evidence indicates that PABP2 may have an additional role in export of mRNA from the nucleus to the cytoplasm (19,20) and in this regard the presence of poly(A) RNA in the OPMD nuclear inclusions may represent mRNA sequestered by the insoluble PABP2 polymers. This raises the possibility that OPMD nuclear inclusions are ‘mRNA traps’, which prevent the transfer of some key mRNA species to the cytoplasm. Depending on the relative transcription and turnover rates of different mRNA species, in particular those that are specifically expressed in the severely affected muscles, some protein levels may become inadequate and lead to cell death. Further experiments are needed to test this hypothesis. However, these observations on a GCG/polyalanine triplet repeat disease may shed new insight on the larger field of the aggregation of proteins with homopolymeric domain expansions.
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MATERIALS AND METHODS |
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Immunofluorescence and in situ hybridization
Immunofluorescence and in situ hybridization were performed on 5–10 µm transverse cryostat sections of frozen diagnostic muscle biopsies. The biopsies were obtained with informed consent, from the deltoid muscle. The samples were frozen without fixation by quick immersion in isopentane chilled in liquid nitrogen and then stored at –80°C. Sections were mounted on slides and were fixed in 3.7% formaldehyde in phosphate-buffered saline (PBS) for 10 min and washed (three times for 10 min each) in PBS containing 0.1 M glycine. The sections were then rinsed in PBS containing 0.1% Tween 20 (PBST) and incubated with primary antibodies in a humid chamber for 30 min at room temperature. After washing in PBST (three times for 15 min each), the samples were incubated with appropriate secondary antibodies for 30 min, washed in PBST (twice for10 min each), rinsed in PBS (5 min) and mounted in Vectashield (Vector, Peterborough, UK). Secondary antibodies conjugated to FITC or TexasRed, were obtained from Jackson ImmunoResearch (West Grove, PA). Staining of double-stranded nucleic acids was performed using the monomeric cyanine dye To-Pro iodide (Molecular Probes, Eugene, OR), diluted to 1 µM in PBS.
In situ hybridization was performed using biotinylated 2'-O-alkyl oligoribonucleotide probes (63). The sequence of the anti-28S rRNA probe was 5'-AIAICCAAUCCUUAUdT-3'; the poly(U) probe contained 20 tandem uridine residues. Fixed samples were rinsed in 6x SSPE (0.9 M NaCl, 0.06 M NaH2PO4, 6 mM EDTA, pH7.4) containing 0.01% Tween 20 and incubated for 30 min in 10 µl of 0.5 mg/ml tRNA, 6x SSPE and 5x Denhardt’s. Hybridization was performed by adding 10 µl of the specific probe diluted to 2 pM/µl in 6x SSPE, 5x Denhardt’s. Hybridization was carried out for 1 h at room temperature, in a humid chamber. After washing (three times for 15 min each in 6x SSPE; twice for 5 min each in 4x SSC, 0.1% Tween 20), the sections were incubated with FITC–avidin.
Confocal microscopy was performed with a Zeiss laser scanning microscope LSM 510, equipped with an argon ion laser (488 nm) to excite FITC fluorescence and a helium–neon laser (543 nm) to excite TexasRed and To-Pro fluorescence (Carl Zeiss, Jena, Germany). For double labeling experiments, images from the same focal plane were sequentially recorded in different channels and superimposed.
Electron microscopy
For immunoelectron microscopy, muscle biopsies were fixed with 3.7% paraformaldehyde in HPEM buffer (30 mM HEPES, 65 mM Pipes, 10 mM EGTA, 2 mM MgCl2, pH 6.9) for 3 h at 4°C, dehydrated in increasing concentrations of methanol at –20°C and embedded in Lowicryl K4M (Polysciences, Warrington, PA) at –20°C. Ultrathin sections were sequentially incubated with 0.1 M glycine in PBS for 15 min, with 5% bovine serum albumin (BSA) in PBS for 15 min and finally the primary antibody diluted in 0.1% BSA in PBS (1 h at room temperature). After washing, the sections were incubated with appropriate secondary antibody conjugated to 5 nm gold particles (BioCell, UK) diluted 1:25 in 0.1% BSA in PBS for 45 min at room temperature. After washing, the sections were stained with 10% aqueous uranyl acetate. The sections were examined with a JEOL CXII electron microscope (JEOL, Tokyo, Japan) operated at 80 kV.
Antibodies
PABP2 was visualized using a polyclonal serum previously described by Krause et al. (22). Affinity-purified antibodies were obtained using recombinant PABP2, expressed in Escherichia coli from plasmid pGM10-PABP2 (64). Additionally, rabbit antibodies, anti-ubiquitin (Dako, Copenhagen, Denmark) and anti-20S proteasome (65) were used.
3'-labeling of RNA
Fluorescence-activated cell sorted myoblast cultures were obtained from surgical specimens (66). Poly(A) mRNA was isolated using the Micopoly(A) Pure mRNA Isolation kit (Ambion, Austin, TX). RNA was labeled in essence, as described by Preker et al. (67). RNA samples [200 ng of poly(A) mRNA or 2 µg of total RNA, respectively, in a volume of 3 µl H2O] were lyophilized in the presence of 5 µl of ethanol. After addition of 12 µl of reaction mix containing 20 mM Tris–HCl pH 7.0, 50 mM KCl, 0.7 mM MnCl2, 10% glycerol, 40 µg/ml methylated BSA, 10 µCi [32P]cordycepin-triphosphate (NEN Life Science, Zaventem, Belgium) and 100 ng of yeast poly(A) polymerase (PAP1p), the samples were incubated for 30 min at 30°C. The reaction was stopped by heat inactivation for 3 min at 90°C. Radioactivity incorporated into RNA was determined by absorption onto DEAE filters. Gel-purified dephosphorylated poly(A) was 5'-labeled with T4 polynucleotide kinase (New England Biolabs, Frankfurt, Germany) and internally labeled L3pre was made by in vitro transcription using [-32P]UTP as described by Wahle (24).
RNAse digestion
Equal amounts of radioactively labeled samples (120 000 c.p.m.) were incubated for 30 min at 30°C in 80 µl reaction mix, containing 2 µg of RNase A (Serva, Heidelberg, Germany) and 50 U RNase T1 (Gibco BRL) in 10 mM Tris–HCl, pH 8.0, 300 mM NaCl and 0.38 µg/µl yeast RNA (Roche Diagnostics, Mannheim, Germany). The digestions were stopped by addition of 20 µl stop-mix containing 5% SDS, 50 mM EDTA, 0.25 µg/µl glycogen (Roche Diagnostics) and 1 µg/µl proteinase K (Merck, Darmstadt, Germany) and 30 min incubation at 37°C. After ethanol precipitation, the RNA was analyzed on 10% polyacrylamide gel containing 8.3 M urea, by the use of phosphor-imaging (Molecular Dynamics, Sunnyvale, CA).
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ACKNOWLEDGEMENTS |
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We thank the patients who partook in this study. We further wish to acknowledge Mrs Dora Brito (University of Lisbon, Portugal) for technical support. We are also grateful to Prof. J. Castaño (University of Madrid, Spain) for generously providing anti-proteasome antibodies and Prof. A. Lamond (University of Dundee, UK) for poly(U) and 28S riboprobes. This study was supported by grants from Fundação para a Ciência e Tecnologia (Portugal), the European Union (BMH4-98-3147), the Canadian Muscular Dystrophy Associations, the American Muscular Dystrophy Associations and the Association Française contre les Myopathies. A.C. is a fellow from the Gulbenkian PhD Program (Portugal). B.B. is a Chercheur-boursier du Fonds de Recherche en Santé du Québec. G.A.R. is supported by the Medical Research Council of Canada. U.K. and E.W. are supported by the Deutsche Forschungsgemeinschaft and Fonds der Chemischen Industrie.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +351 21 7934340; Fax: +351 21 7951780; Email: carmo.fonseca@fm.ul.pt
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