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Nuclear entrapment and extracellular depletion of PCOLCE is associated with muscle degeneration in oculopharyngeal muscular dystrophy
- Vered Raz†1Email author,
- Ellen Sterrenburg†1,
- Samantha Routledge†2,
- Andrea Venema1,
- Barbara M van der Sluijs3,
- Capucine Trollet4, 5,
- George Dickson4,
- Baziel GM van Engelen3,
- Silvère M van der Maarel1 and
- Michael N Antoniou2Email author
© Raz et al.; licensee BioMed Central Ltd. 2013
Received: 21 June 2012
Accepted: 20 June 2013
Published: 1 July 2013
Muscle fibrosis characterizes degenerated muscles in muscular dystrophies and in late onset myopathies. Fibrotic muscles often exhibit thickening of the extracellular matrix (ECM). The molecular regulation of this process is not fully understood. In oculopharyngeal muscular dystrophy (OPMD), an expansion of an alanine tract at the N-terminus of poly(A)-binding protein nuclear 1 (PABPN1) causes muscle symptoms. OPMD patient muscle degeneration initiates after midlife, while at an earlier age carriers of alanine expansion mutant PABPN1 (expPABPN1) are clinically pre-symptomatic. OPMD is characterized by fibrosis in skeletal muscles but the causative molecular mechanisms are not fully understood.
We studied the molecular processes that are involved in OPMD pathology using cross-species mRNA expression profiles in muscles from patients and model systems. We identified significant dysregulation of the ECM functional group, among which the procollagen C-endopeptidase enhancer 1 gene (PCOLCE) was consistently down-regulated across species. We investigated PCOLCE subcellular localization in OPMD muscle samples and OPMD model systems to investigate any functional relevance of PCOLCE down-regulation in this disease.
We found that muscle degeneration in OPMD is associated with PCOLCE down-regulation. In addition to its known presence at the ECM, we also found PCOLCE within the nucleus of muscle cells. PCOLCE sub-cellular localization changes during myoblast cell fusion and is disrupted in cells expressing mutant expPABPN1. Our results show that PCOLCE binds to soluble PABPN1 and co-localizes with aggregated PABPN1 with a preference for the mutant protein. In muscle biopsies from OPMD patients we find that extracellular PCOLCE is depleted with its concomitant enrichment within the nuclear compartment.
PCOLCE regulates collagen processing at the ECM. Depletion of extracellular PCOLCE is associated with the expression of expPABPN1 in OPMD patient muscles. PCOLCE is also localized within the nucleus where it binds to PABPN1, suggesting that PCOLCE shuttles between the ECM and the nucleus. PCOLCE preferentially binds to expPABPN1. Nuclear-localized PCOLCE is enriched in muscle cells expressing expPABPN1. We suggest that nuclear entrapment of PCOLCE and its extracellular depletion represents a novel molecular mechanism in late-onset muscle fibrosis.
KeywordsOPMD Extracellular matrix PCOLCE Muscle fibrosis PABPN1
The extracellular matrix (ECM) plays a key role in regulating homeostasis and tissue repair. Wound healing and fibrosis are highly regulated by the ECM . The ECM surrounding skeletal muscle tissue maintains cellular function and fibre structure, and further provides an environment for muscle fibre contraction. Defects or deficiencies in molecules that reside in the ECM can cause skeletal muscle myopathy and muscle fibrosis . Fibrotic muscle tissue exhibits an excess accumulation of collagen and other ECM components , leading to aberrant muscle fibre function . The role of the ECM in muscle function has been extensively studied in Duchene muscular dystrophy (DMD). DMD is caused by mutations in the gene that encodes Dystrophin, a mechanical transducer muscle protein that transmits external stimuli into the cell. When Dystrophin is mutated, signals from the ECM are poorly transduced into the cell . Nevertheless, the molecular mechanisms that are associated with changes in the ECM in different myopathies are not fully understood.
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, usually autosomal dominantly inherited myopathy . In OPMD muscle weakness is progressive and initially affects muscles of the eyelid, throat and proximal limbs. OPMD patients harbour a triplet repeat expansion mutation in the gene encoding poly(A)-binding protein nuclear 1 (PABPN1), leading to an expansion of the poly-alanine (poly-Ala) tract at the N-terminus of PABPN1 . Alanine expanded PABPN1 (expPABPN1) is prone to aggregation and forms insoluble inclusions within the nuclei of skeletal muscle fibres in OPMD patients . In addition, OPMD muscles contain rimmed vacuoles, which are a characteristic of fibrotic muscles . Fibrotic muscles were also reported in a mouse model of OPMD that over expresses expPABPN1 in skeletal muscles [10, 11]. To date, ECM defects and their potential contribution to OPMD muscle symptoms have not been investigated.
Here we report deregulation of the ECM functional group in OPMD Vastus lateralis (VL) muscles. Dysrgulation of the ECM was consistent in model systems for OPMD. We focused on procollagen C-proteinase enhancer 1 (PCOLCE; PCPE-1) as it was found to be consistently deregulated in OPMD patients and in a muscle cell model system of this condition. PCOLCE is predominantly localised at the ECM, where it functions as a positive regulator of collagen deposition . Nuclear-localised PCOLCE co-immunoprecipitates with soluble expPABPN1 and co-localises with aggregated PABPN1. In both cell and animal model systems of OPMD that express expPABPN1, PCOLCE retention in the nucleus was concomitant with reduced accumulation in the ECM. We suggest that nuclear entrapment of PCOLCE is associated with its extracellular depletion, and hence represents a novel mechanism by which this protein is involved in muscle fibrosis.
Cell culture and collection of muscle biopsies
An ImmortoMouse-derived myoblast cell clone, designated IM2, was produced as previously described , and used to generate stably transfected clones expressing either normal Ala10-humanPABPN1-FLAG (Ala10) or mutant Ala17-humanPABPN1-FLAG (Ala17) . Cells were maintained in a proliferating medium containing DMEM (Invitrogen, Carlsbad, CA, USA), supplemented with 20% foetal calf serum (FCS) (Invitrogen), 0.5% chicken embryo extract (PAA laboratories, Somerset, UK), 100 U/ml penicillin/streptomycin, 2 mM L-glutamine and 20 U/ml IFNγ (HyCult Biotech, Uden, The Netherlands) at 33°C in a humidified 10% CO2-air atmosphere. Myoblast fusion was conducted with confluent cultures maintained in fusion medium consisting of DMEM containing 5% horse serum without IFNγ and incubation at 37°C in a humidified 5% CO2-air atmosphere for up to 5 days. Details of the generation of the Ala10 and Ala17 IM2-derived clones used in this study have been previously described .
Clinical description of OPMD patients and pre-symptomatic carriers contributing to this study
Protein analysis and detection procedures
Total protein extracts from unfused myoblast and fused myotube cultures were produced by direct lysis in sodium dodecyl sulphate (SDS) loading buffer (50 mM Tris pH 6.8, 10 mM DTT, 2% SDS, 0.1% bromophenol blue, 20% glycerol). Samples were resolved by 10% polyacrylamide gel electrophoresis (PAGE) under denaturing conditions followed by Western blot analysis.
Immonoprecipitation of soluble proteins was conducted with protein extracts from 4-day fused myoblast cultures. Proteins were extracted with a buffer containing 150 mM NaCl, 50 mM Tris pH7.5, 0.1% Tween and protease inhibitor cocktail (Sigma-Aldrich, Saint Louis, Missouri, USA). FLAG-tagged PABPN1 protein in these extracts was bound with rabbit-anti FLAG (Sigma-Aldrich) antibodies and precipitated with Protein-A Sepharose (Sigma-Aldrich). After extensive washing with decreasing NaCl concentrations (150-0 mM), loading buffer was added and samples resolved by 10% SDS-PAGE followed by Western blot analysis.
Western blot analysis was conducted by a transfer of SDS-PAGE resolved products onto PVDF membranes. Detection of primary antibodies was conducted after incubation with horseradish peroxidase (HRP)-conjugated secondary antibodies with the Amersham Hybond ECL chemiluminescence detection system (GE Healthcare Bio-Sciences AB, Uppsala, Sweden).
Histological staining and immunofluorescence analysis of myotube cultures was performed as previously described . Human skeletal muscle cryosections were generated from biopsy samples of VL muscles from both healthy controls and OPMD patients after informed consent. Mouse muscle sections were generated from Tibialis anterior (TA) muscles from wild type or A17.1 OPMD model mice  at 12, 18 and 26 weeks of age. Sections were fixed in PBS/3.7% formaldehyde for 30 minutes followed by permeabilisation with 1% Triton-X100 for 30 min and washing with PBS following antibody incubations as above.
Treatment with 1 M KCl was for 20 minutes and preceded tissue fixation. Human muscle sections were incubated with 0.3% Sudan Black B (Sigma-Aldrich) for 10 min to eliminate background from intrinsic autofluorescent pigments. After completion of antibody staining steps, samples were overlaid with cover-slips mounted in Vectashield (Vector, Peterborough, UK) or Vectashield containing 4′-6-diamidino-2-phenylindole (Sigma-Aldrich) at a concentration of 3 ng/l. Images were recorded with a Zeiss Axiovert (model 135TV) fluorescence microscope equipped with a 100-W mercury arc lamp and a 40x/1.3 NA plan Apo objective. Single confocal sections were obtained with a Leica TCS/SP2 confocal microscope system equipped with a 100x/1.4 NA plan Apo objective.
For histological staining, human specimens were processed for light microscopic investigation and stained with haematoxylin-eosin.
Primary antibodies used were: mouse monoclonal anti-FLAG M2 (Sigma-Aldrich); mouse monoclonal anti-muscle actin (MSA) (Novocastra, Newcastle upon Tyne, UK); mouse monoclonal anti-α-Tubulin (Sigma-Aldrich); mouse anti-ubiquitin, FK2, (AbCam, Cambridge, UK); rabbit polyclonal anti-Pcolce (AbCam and Sigma-Aldrich); mouse anti-Dysferlin (Novocastra); anti-MBNL1 (donated by Dr. T.A. Cooper Baylor College of Medicine, Houston, USA), Myc-tagged 3 F5 llama single chain antibody , which is recognised with mouse-anti-Myc clone SE50 (Sigma-Aldrich) at dilutions 1:1000–3000. Alexa 488-, Alexa 430- or Alexa 594- conjugated secondary antibodies against primary antibodies were obtained from Molecular Probes (Invitrogen).
Image quantification was performed with ImageJ application (http://rsbweb.nih.gov/ij/).
RNA expression and transcriptome analysis
Bioinformatics analysis of the datasets was as previously described and is publically available . Analysis of OPMD-deregulated ECM pathways was performed with DAVID, functional annotation clustering tool , and statistical analysis of deregulated pathways was performed with Globaltest. PCOLCE expression values were obtained from a list of OPMD-deregulated top tables (p < 0.05), comparing expression levels in VL muscles of OPMD and an age-matched control group .
Primers used for quantitative RT-qPCR
Significant ECM deregulation in OPMD
Pcolce expression is consistently down-regulated in a murine myotube culture model of OPMD
Nuclear Pcolce co-localises in nuclear aggregates and co-immunoprecipitates with expPABPN1
Formation of expPABPN1 nuclear aggregates is the hallmark of OPMD. Therefore, we next investigated whether PCOLCE co-localises with PABPN1 within nuclear aggregates. Aggregated PABPN1 forms distinct fluorescent foci and co-localization with candidate proteins could be determined using intensity distribution plots . We identified that Pcolce co-localises with PABPN1 in fluorescent foci in the skeletal myoblast cell model system (Figure 4Aii). Co-localization was more pronounced in fluorescent foci formed by expPABPN1 compared with those consisting of wild type PABPN1 (Figure 4Aii). This suggests that PCOLCE binds to nuclear PABPN1 and with a preference for expPABPN1 compared to the wild type protein. Analysis by immunoprecipitation of soluble protein extracts from myotube cultures with an anti-FLAG antibody that recognises transgene-derived Ala10- or Ala17- PABPN1-FLAG, revealed that Pcolce co-immunoprecipites with PABPN1 (Figure 4B). Full-length (48 kDa) Pcolce protein co-immunoprecipitated with both Ala10- and Ala17- PABPN1-FLAG, but there was a clear enrichment in binding between Pcolce and mutant Ala17-PABPN1 compared to that with wild type Ala10 PABPN1 (Figure 4B). These results show that Pcolce binds to soluble PABPN1 but with a higher affinity to expPABPN1.
Pcolce localisation is reduced at the ECM and is retained in the nucleus in the OPMD mouse model and in OPMD VLmuscles
To confirm that nuclear PCOLCE co-localizes with aggregated PABPN1, muscle sections were treated with 1 M KCl to remove most soluble nuclear proteins. Aggregated nuclear proteins are resistant to KCl treatment and are present as intense fluorescence foci, whilst soluble proteins are observed as a diffuse signal. However, it should be noted that the severity of the treatment with 1 M KCl disrupts the morphology of the cell nucleus. Nevertheless, in the section of OPMD patient muscle (Figure 7B, lower panel), two nuclei are shown. In one nucleus the PABPN1 inclusion encompasses most of the nucleus within which PCOLCE is co-localized with aggregated PABPN1 (Figure 7B, lower panel, arrow). In the other nucleus, accumulation of aggregated PABPN1 is far more limited and PCOLCE co-localization is also reduced. This suggests that PCOLCE entrapment within PABPN1 nuclear aggregates is consistent between OPMD patient and cellular (Figure 4A) and animal (Figure 5) model systems. In marked contrast to the paucity of nuclear aggregates in OPMD myonuclei (1-5%; [8, 23]), the reduction in extracellular PCOLCE and its nuclear enrichment was uniformly distributed throughout the muscle section from the OPMD patient (Figure 7C). Collectively, our data from the OPMD cell and animal model systems combined with that obtained from patient VL muscle biopsy samples, highlights a change in the sub-cellular distribution of PCOLCE in OPMD.
Discussion and conclusion
ECM defects are associated with muscle fibrosis of muscular disorders, and are usually detected at a progressed state of the disease. Muscular dystrophies including OPMD are characterised by the presence of fibrotic muscles. Deregulation of the ECM is found in inherited degenerative muscle diseases such as DMD, FSHD and α-sarcoglycan deficiency [24–26]. ECM thickening in DMD patients are associated with significant dysregulation of collagen and other ECM protein genes . Muscles from symptomatic patients show ECM thickening that is typical of fibrotic tissue. Collagen type I and III are major components of the ECM in skeletal muscle , and in inherited muscular dystrophies an up-regulation of collagen-encoding genes is associated with thickening of the ECM. ECM thickening affects muscle contraction and extracellular signal transduction and increased inflammation . In DMD patients, ECM thickening is associated with up-regulation of collagen encoding genes . Similar to other muscle disorders, in OPMD we found significant molecular dysregulation of ECM-associated genes. Since dysregulation of ECM encoding genes in different cell types are often associated with ECM thickening and profibrotic situations , it is highly likely that the transcriptional changes in the ECM functional group in OPMD are associated with muscle degeneration.
We identified consistent down-regulation of PCOLCE in OPMD patient and cellular and mouse model systems of this condition. In carriers of expPABPN1, down-regulation was found in symptomatic patients but not at the pre-symptomatic stage of the disease. This suggests that the change in PCOLCE expression in muscles is associated with muscle degeneration. PCOLCE is down-regulated in OPMD and is found in PABPN1 nuclear aggregates. Products of dysregulated genes in model systems expressing expPABPN1 often co-localize with PABPN1 within nuclear aggregates [16, 29]. The mechanism as to how this occurs is not fully understood. However, it is possible that a feedback-forward regulatory mechanism between protein aggregation and mRNA accumulation is disturbed when aggregates are formed.
The procollagen I peptide is proteolytically processed to form collagen fibres. Extracellular PCOLCE stimulates the function of procollagen C-proteinase, thereby leading to increased cleavage and processing of procollagen I proteins . Pcolce deficient mice exhibit ECM thickening, aberrant procollagen peptide processing and deformed collagen fibril morphology . Taken together these processes suggest that a reduction in PCOLCE at the extracellular matrix would diminish collagen fibrillogenesis and hence negatively affect ECM maintenance . Of relevance to muscle disorders, Pcolce down-regulation has been found in Myostatin-knockdown mice, and was associated with reduced collagen content and muscle fibrosis . It is therefore likely that in OPMD a reduced expression of PCOLCE causes ECM thickening and consequently contributes to muscle fibrosis.
PCOLCE is a secreted protein. It is synthesized in the lumen of the ER and is transported to the extracellular compartment via the Golgi apparatus and associated secretion pathway . In addition to its known extracellular location at the ECM, we found PCOLCE to also be present within the cell nucleus. We found that PCOLCE sub-cellular localization is dynamic in muscle cells, and changed upon myoblast differentiation to fused myotubes. In degenerated OPMD muscles, a reduction in extracellular PCOLCE is associated with retention of this protein within the nucleus. Since PCOLCE protein biosynthesis is at the secretary Golgi apparatus, this suggests that PCOLCE may shuttle from the extracellular into the cell nuclear compartment. However, the mechanism regulating PCOLCE sub-cellular localization remains to be investigated.
We found that PABPN1 co-immunoprecipitates with PCOLCE (Figure 4B). Since PABPN1 is predominantly localized within the cell nucleus and we found co-localization of PABPN1 and PCOLCE within this sub-cellular compartment (Figures 4A, 5 and 7B), we conclude that PCOLCE binds to nuclear PABPN1 and consequently is entrapped in PABPN1 aggregates.
Co-localization between PCOLCE and aggregated PABPN1 was found to be consistent between cellular and animal model systems of OPMD as well as within OPMD patient muscle samples. Protein entrapment within PABPN1 inclusions is a gradual process where proteins such as ubiquitin or poly(A) polymerase co-localize with small and intermediate sized aggregates, whilst others like heat-shock protein 70 (HSP70) are recruited to large and non-reversible aggregates . Since only limited co-localization of PCOLCE and PABPN1 was found in OPMD nuclei with reduced amounts of aggregated PABPN1 (Figure 7B), it is likely that PCOLCE, as in the case of HSP70, is also recruited to inclusions but not to the intermediate sized PABPN1 aggregated structures.
PABPN1 is a regulator of mRNA processing [32–35]. A functional role for nuclear PCOLCE is, as yet, unknown. PCOLCE contains RNA binding motifs and a role in RNA stabilisation has been suggested . Here we show that PCOLCE binding to PABPN1 is enriched in cells expressing mutant expPABPN1. This suggests that PCOLCE binding to PABPN1 is of relevance to OPMD pathogenesis. It is possible that due to the alanine expansion in expPABPN1 the dynamics of the PCOLCE-PABPN1 complex is reduced and that this in turn could negatively affect PABPN1 function.
In contrast to the paucity of PABPN1 nuclear aggregate formation in affected myonuclei [8, 23], we found a consistent reduction in ECM-localised PCOLCE levels across muscle fibres of OPMD patients, and in a mouse model of this disease. This consistency suggests that this feature could be employed as a marker of affected muscles in OPMD patients. In a skeletal myoblast cell model system expressing expPABPN1, we observed accumulation of nuclear PCOLCE and co-localisation of PCOLCE with aggregated PABPN1. This observation was confirmed in OPMD patient muscle biopsy samples, where nuclear PCOLCE accumulation was more prominent compared with that seen in a healthy control or other muscular dystrophies, namely DMD and FSHD. As both OPMD and MD1 are classified as late onset disease conditions whilst DMD starts within childhood and symptoms in FSHD are typically observed from around 20 years of age, it is possible that the change in PCOLCE sub-cellular localisation may be of greater relevance to late onset muscle disorders. However, the contribution of dysregulation of PCOLCE sub-cellular localisation to disease pathophysiology remains to be demonstrated.
We thank H.J. Ter Laak (Pathology Department, Nijmegen, Netherlands) for providing patient muscle sections and David C. Rubinsztein for providing us with the A17.1 OPMD mice. Our studies were supported by funds from the European Commission (TRI-EX QLG2-CT-2001-01673 and POLYALA LSHM-CT-2005-018675), the Muscular Dystrophy Association (Nr. 68015) and the Association France for Myopathy (Nr. 15 123).
- Raghow R: The role of extracellular matrix in postinflammatory wound healing and fibrosis. FASEB J. 1994, 8 (11): 823-831.PubMedGoogle Scholar
- Voermans NC, Bonnemann CG, Huijing PA, Hamel BC, Van Kuppevelt TH, De Haan A, Schalkwijk J, Van Engelen BG, Jenniskens GJ: Clinical and molecular overlap between myopathies and inherited connective tissue diseases. Neuromuscul Disord. 2008, 18 (11): 843-856. 10.1016/j.nmd.2008.05.017.View ArticlePubMedGoogle Scholar
- Rampoldi E, Meola G, Conti AM, Velicogna M, Larizza L: A comparative analysis of collagen III, IV, laminin and fibronectin in Duchenne muscular dystrophy biopsies and cell cultures. Eur J Cell Biol. 1986, 42 (1): 27-34.PubMedGoogle Scholar
- Serrano AL, Munoz-Canoves P: Regulation and dysregulation of fibrosis in skeletal muscle. Exp Cell Res. 2010, 316 (18): 3050-3058. 10.1016/j.yexcr.2010.05.035.View ArticlePubMedGoogle Scholar
- Mann CJ, Perdiguero E, Kharraz Y, Aguilar S, Pessina P, Serrano AL, Munoz-Canoves P: Aberrant repair and fibrosis development in skeletal muscle. Skelet Muscle. 2011, 1 (1): 21-10.1186/2044-5040-1-21.View ArticlePubMedPubMed CentralGoogle Scholar
- Brais B: Oculopharyngeal muscular dystrophy: a polyalanine myopathy. Curr Neurol Neurosci Rep. 2009, 9 (1): 76-82. 10.1007/s11910-009-0012-y.View ArticlePubMedGoogle Scholar
- Brais B, Bouchard JP, Xie YG, Rochefort DL, Chretien N, Tome FM, Lafreniere RG, Rommens JM, Uyama E, Nohira O, et al: Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet. 1998, 18 (2): 164-167. 10.1038/ng0298-164.View ArticlePubMedGoogle Scholar
- Tome FM, Fardeau M: Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuropathol. 1980, 49 (1): 85-87. 10.1007/BF00692226.View ArticlePubMedGoogle Scholar
- Coquet M, Vital C, Julien J: Presence of inclusion body myositis-like filaments in oculopharyngeal muscular dystrophy. Ultrastructural study of 10 cases. Neuropathol Appl Neurobiol. 1990, 16 (5): 393-400. 10.1111/j.1365-2990.1990.tb01275.x.View ArticlePubMedGoogle Scholar
- Davies JE, Wang L, Garcia-Oroz L, Cook LJ, Vacher C, O‘Donovan DG, Rubinsztein DC: Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice. Nat Med. 2005, 11 (6): 672-677. 10.1038/nm1242.View ArticlePubMedGoogle Scholar
- Trollet C, Anvar SY, Venema A, Hargreaves IP, Foster K, Vignaud A, Ferry A, Negroni E, Hourde C, Baraibar MA, et al: Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres. Hum Mol Genet. 2010, 19 (11): 2191-2207. 10.1093/hmg/ddq098.View ArticlePubMedGoogle Scholar
- Kessler E, Mould AP, Hulmes DJ: Procollagen type I C-proteinase enhancer is a naturally occurring connective tissue glycoprotein. Biochem Biophys Res Commun. 1990, 173 (1): 81-86. 10.1016/S0006-291X(05)81024-1.View ArticlePubMedGoogle Scholar
- Morgan NS, Heintzelman MB, Mooseker MS: Characterization of myosin-IA and myosin-IB, two unconventional myosins associated with the Drosophila brush border cytoskeleton. Dev Biol. 1995, 172 (1): 51-71. 10.1006/dbio.1995.0005.View ArticlePubMedGoogle Scholar
- Raz V, Routledge S, Venema A, Buijze H, van der Wal E, Anvar S, Straasheijm KR, Klooster R, Antoniou M, van der Maarel SM: Modeling oculopharyngeal muscular dystrophy in myotube cultures reveals reduced accumulation of soluble mutant PABPN1 protein. Am J Pathol. 2011, 179 (4): 1988-2000. 10.1016/j.ajpath.2011.06.044.View ArticlePubMedPubMed CentralGoogle Scholar
- Verheesen P, De Kluijver A, Van Koningsbruggen S, De Brij M, De Haard HJ, Van Ommen G-JB, van der Maarel SM, Verrips CT: Prevention of oculopharyngeal muscular dystrophy-associated aggregation of nuclear poly(A)-binding protein with a single-domain intracellular antibody. Hum Mol Genet. 2006, 15 (1): 105-111.View ArticlePubMedGoogle Scholar
- Anvar SY, Hoen PA T, Venema A, van der Sluijs B, Van Engelen B, Snoeck M, Vissing J, Trollet C, Dickson G, Chartier A, et al: Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients. Skelet Muscle. 2011, 1: 1-15. 10.1186/2044-5040-1-1.View ArticleGoogle Scholar
- Dennis G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA: DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003, 4 (5): P3-10.1186/gb-2003-4-5-p3.View ArticlePubMedGoogle Scholar
- Goeman JJ, van de Geer SA, De Kort F, Van Houwelingen HC: A global test for groups of genes: testing association with a clinical outcome. Bioinformatics. 2004, 20 (1): 93-99. 10.1093/bioinformatics/btg382.View ArticlePubMedGoogle Scholar
- Sluijs B, Hoefsloot L, Padberg G, Maarel S, Engelen BM: Oculopharyngeal muscular dystrophy with limb girdle weakness as major complaint. J Neurol. 2003, 250 (11): 1307-1312. 10.1007/s00415-003-0201-6.View ArticleGoogle Scholar
- Hopkins DR, Keles S, Greenspan DS: The bone morphogenetic protein 1/Tolloid-like metalloproteinases. Matrix Biol. 2007, 26 (7): 508-523. 10.1016/j.matbio.2007.05.004.View ArticlePubMedPubMed CentralGoogle Scholar
- Takahara K, Kessler E, Biniaminov L, Brusel M, Eddy RL, Jani-Sait S, Shows TB, Greenspan DS: Type I procollagen COOH-terminal proteinase enhancer protein: identification, primary structure, and chromosomal localization of the cognate human gene (PCOLCE). J Biol Chem. 1994, 269 (42): 26280-26285.PubMedGoogle Scholar
- Raz V, Abraham T, Van Zwet EW, Dirks RW, Tanke HJ, van der Maarel SM: Reversible aggregation of PABPN1 pre-inclusion structures. Nucleus. 2011, 2 (3): 208-218. 10.4161/nucl.2.3.15736.View ArticlePubMedPubMed CentralGoogle Scholar
- Calado A, Tome FM, Brais B, Rouleau GA, Kuhn U, Wahle E, Carmo-Fonseca M: Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA. Hum Mol Genet. 2000, 9 (15): 2321-2328. 10.1093/oxfordjournals.hmg.a018924.View ArticlePubMedGoogle Scholar
- Haslett JN, Sanoudou D, Kho AT, Bennett RR, Greenberg SA, Kohane IS, Beggs AH, Kunkel LM: Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle. Proc Natl Acad Sci U S A. 2002, 99 (23): 15000-15005. 10.1073/pnas.192571199.View ArticlePubMedPubMed CentralGoogle Scholar
- Noguchi S, Tsukahara T, Fujita M, Kurokawa R, Tachikawa M, Toda T, Tsujimoto A, Arahata K, Nishino I: cDNA microarray analysis of individual Duchenne muscular dystrophy patients. Hum Mol Genet. 2003, 12 (6): 595-600. 10.1093/hmg/ddg065.View ArticlePubMedGoogle Scholar
- Winokur ST, Chen YW, Masny PS, Martin JH, Ehmsen JT, Tapscott SJ, van der Maarel SM, Hayashi Y, Flanigan KM: Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation. Hum Mol Genet. 2003, 12 (22): 2895-2907. 10.1093/hmg/ddg327.View ArticlePubMedGoogle Scholar
- Bosman FT, Stamenkovic I: Functional structure and composition of the extracellular matrix. J Pathol. 2003, 200 (4): 423-428. 10.1002/path.1437.View ArticlePubMedGoogle Scholar
- Zheng J, Chen Y, Pat B, Dell‘italia LA, Tillson M, Dillon AR, Powell PC, Shi K, Shah N, Denney T, et al: Microarray identifies extensive downregulation of noncollagen extracellular matrix and profibrotic growth factor genes in chronic isolated mitral regurgitation in the dog. Circulation. 2009, 119 (15): 2086-2095. 10.1161/CIRCULATIONAHA.108.826230.View ArticlePubMedPubMed CentralGoogle Scholar
- Corbeil-Girard LP, Klein AF, Sasseville AM, Lavoie H, Dicaire MJ, Saint-Denis A, Page M, Duranceau A, Codere F, Bouchard JP, et al: PABPN1 overexpression leads to upregulation of genes encoding nuclear proteins that are sequestered in oculopharyngeal muscular dystrophy nuclear inclusions. Neurobiol Dis. 2005, 18 (3): 551-567. 10.1016/j.nbd.2004.10.019.View ArticlePubMedGoogle Scholar
- Steiglitz BM, Kreider JM, Frankenburg EP, Pappano WN, Hoffman GG, Meganck JA, Liang X, Hook M, Birk DE, Goldstein SA, et al: Procollagen C proteinase enhancer 1 genes are important determinants of the mechanical properties and geometry of bone and the ultrastructure of connective tissues. Mol Cell Biol. 2006, 26 (1): 238-249. 10.1128/MCB.26.1.238-249.2006.View ArticlePubMedPubMed CentralGoogle Scholar
- Welle S, Cardillo A, Zanche M, Tawil R: Skeletal muscle gene expression after myostatin knockout in mature mice. Physiol Genomics. 2009, 38 (3): 342-350. 10.1152/physiolgenomics.00054.2009.View ArticlePubMedPubMed CentralGoogle Scholar
- De Klerk E, Venema A, Anvar SY, Goeman JJ, Hu O, Den Dunnen JT, van der Maarel SM, Raz V, Aòt H: PAC: Poly(A) binding protein nuclear 1 levels affect alternative polyadenylation. Nucleic Acids Res. 2012, 40 (18): 9089-9101. 10.1093/nar/gks655.View ArticlePubMedPubMed CentralGoogle Scholar
- Jenal M, Elkon R, Loayza-Puch F, Van Haaften G, Khn U, Menzies FM, Vrielink JAFO, Bos AJ, Drost J, Rooijers K, et al: The Poly(A)-Binding Protein Nuclear 1 Suppresses Alternative Cleavage and Polyadenylation Sites. Cell. 2012, 149 (3): 538-553. 10.1016/j.cell.2012.03.022.View ArticlePubMedGoogle Scholar
- Apponi LH, Leung SW, Williams KR, Valentini SR, Corbett AH, Pavlath GK: Loss of nuclear poly(A)-binding protein 1 causes defects in myogenesis and mRNA biogenesis. Hum Mol Genet. 2010, 19 (6): 1058-1065. 10.1093/hmg/ddp569.View ArticlePubMedGoogle Scholar
- Kuhn U, Gundel M, Knoth A, Kerwitz Y, Rudel S, Wahle E: Poly(A) tail length is controlled by the nuclear poly(A)-binding protein regulating the interaction between poly(A) polymerase and the cleavage and polyadenylation specificity factor. J Biol Chem. 2009, 284 (34): 22803-22814. 10.1074/jbc.M109.018226.View ArticlePubMedPubMed CentralGoogle Scholar
- Matsui A, Yanase M, Tomiya T, Ikeda H, Fujiwara K, Ogata I: Stabilization of RNA strands in protein synthesis by type I procollagen C-proteinase enhancer protein, a potential RNA-binding protein, in hepatic stellate cells. Biochem Biophys Res Commun. 2002, 290 (3): 898-902. 10.1006/bbrc.2001.6287.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/13/70/prepub
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