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Progress in Understanding the Pathogenesis of Oculopharyngeal Muscular Dystrophy

Published online by Cambridge University Press:  02 December 2014

Xueping Fan  and
Guy A. Rouleau
Xueping Fan
Affiliation:
Center for Research in Neuroscience, McGill University, and the McGill University Health Center, Montreal, Quebec, Canada
Guy A. Rouleau
Affiliation:
Center for Research in Neuroscience, McGill University, and the McGill University Health Center, Montreal, Quebec, Canada
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Abstract

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Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping (ptosis), swallowing difficulties (dysphagia), and proximal limb weakness. The autosomal dominant form of this disease is caused by expansions of a (GCG)6 repeat to (GCG)8-13 in the PABPN1 gene. These mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminal domain of PABPN1. Mutated PABPN1 (mPABPN1) induces the formation of muscle intranuclear inclusions that are thought to be the hallmark of this disease. In this review, we discuss: 1) OPMD genetics and PABPN1 function studies; 2) diseases caused by polyalanine expansions and cellular polyalanine toxicity; 3) mPABPN1-induced intranuclear inclusion toxicity; 4) role of oligomerization of mPABPN1 in the formation and toxicity of OPMD intranuclear inclusions and; 5) recruitment of subcellular components to the OPMD inclusions. We present a potential molecular mechanism for OPMD pathogenesis that accounts for these observations.

Résumé:

RÉSUMÉ:

La dystrophie musculaire oculopharyngée (DMOP) est une maladie de l’âge adulte caractérisée par une chute progressive de la paupière supérieure (ptose), des difficultés de déglutition (dysphagie) et une faiblesse musculaire proximale. La forme autosomique dominante de la maladie est causée par une expansion de répétitions GCG de 6 à 8-13 répétitions dans le gène PABPN1. Ces mutations provoquent l’expansion d’une séquence de polyalanine de 10 à 12-17 alanines dans le domaine n-terminal de PABPN1. Le gène PABPN1 muté (mPABPN1) entraîne la formation d’inclusions intranucléaires musculaires qui sont considérées comme les stigmates de cette maladie. Dans cette revue, nous discutons: 1) de la génétique de la DMOP et des études de fonction du gène PABPN1; 2) des maladies causées par une expansion polyalanine et de la toxicité cellulaire de la polyalanine; 3) de la toxicité des inclusions intranucléaires dues à mPABPN1; 4) du rôle de l’oligomérisation de mPABPN1 dans la formation et la toxicité des inclusions intranucléaires de la DMOP et 5) du recrutement de composantes subcellulaires aux inclusions de la DMOP. Nous présentons un mécanisme moléculaire de la pathogenèse de la DMOP qui expliquerait toutes ces observations.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 30 , Issue 1 , February 2003 , pp. 8 - 14
Copyright
Copyright © The Canadian Journal of Neurological 2003

References

1. Dreyfuss, G, Matunis, MJ, Pino-Roma, S, Burd, CG. hnRNP proteins and the biogenesis of mRNA. Ann Rev Biochem 1993; 62: 289–321.CrossRefGoogle ScholarPubMed
2. Chen, Z, Li, Y, Krug, R. Influenza A virus NS1 protein targets poly(A)-binding protein II of the cellular 3’-end processing machinery. EMBO J 1999; 18: 2273–2283.CrossRefGoogle ScholarPubMed
3. Bouchard, JP, Gagne, F, Tome, FM, Brunet, D. Nuclear inclusions in oculopharyngeal muscular dystrophy in Quebec. Can J Neurol Sci 1989; 16: 446–450.CrossRefGoogle ScholarPubMed
4. Wahle, E, Kuhn, U. The mechanism of 3’ cleavage and polyadenylation of eukaryotic pre-mRNA. Prog Nucleic Acid Res Mol Biol 1997; 57: 41–71.CrossRefGoogle ScholarPubMed
5. Brown, SA, Warburton, D, Brown, LY, et al. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nat Genet 1998; 20: 180–183.CrossRefGoogle ScholarPubMed
6. Ferrigno, P, Silver, PA. Polyglutamine expansions: proteolysis, chaperones, and the dangers of promiscuity. Neuron 2000; 26: 9–12.CrossRefGoogle ScholarPubMed
7. Kumar, A, Sierakowska, H, Szer, W. Purification and RNA binding properties of a C-type hnRNP protein from HeLa cells. J Biol Chem 1987; 262: 17126–17137.Google ScholarPubMed
8. Wahle, E, Lustig, A, Jeno, P, Maurer, P. Mammalian poly(A)-binding protein II. Physical properties and binding to polynucleotides. J Biol Chem 1993; 268: 2937–2945.Google ScholarPubMed
9. Mundlos, S, Otto, F, Mundlos, C, et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 1997; 89: 773–779.CrossRefGoogle ScholarPubMed
10. Stajich, JM, Gilchrist, JM, Lennon, F, et al. Confirmation of linkage of oculopharyngeal muscular dystrophy to chromosome 14q11.2-q13 in American families suggests the existence of a second causal mutation. Neuromuscul Disord 1997; 7(Suppl 1): S75–S81.CrossRefGoogle ScholarPubMed
11. Khan, FA, Jaiswal, AK, Szer, W. Cloning and sequence analysis of a human type A/B hnRNP protein. FEBS 1991; 290: 159–161.Google ScholarPubMed
12. Calado, A, Tome, FMS, Brais, B, et al. Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA. Hum Mol Genet 2000; 9: 2321–2328.CrossRefGoogle Scholar
13. Shanmugam, V, Dion, P, Rochefort, D, et al. PABP2 polyalanine tract expansion causes intranuclear inclusions in oculopharyngeal muscular dystrophy. Ann Neurol 2000; 48: 798–802.3.0.CO;2-U>CrossRefGoogle ScholarPubMed
14. Kim, YJ, Noguchi, S, Hayashi, YK, et al. The product of an oculopharyngeal muscular dystrophy gene, poly(A)-binding protein 2, interacts with SKIP and stimulates muscle-specific gene expression. Hum Mol Genet 2001; 10: 1129–1139.CrossRefGoogle ScholarPubMed
15. Bienroth, S, Keller, W, Wahle, E. Assembly of a processive messenger RNA polyadenylation complex. EMBO J 1993; 12: 585–594.CrossRefGoogle ScholarPubMed
16. Minvielle-Sebastia, L, Keller, W. mRNA polyadenylation and its coupling to other RNA processing reactions and to transcription. Curr Opin Cell Biol 1999; 11: 352–357.CrossRefGoogle ScholarPubMed
17. Barabino, SML, Keller, W. Last but not least: regulated poly(A) tail formation. Cell 1999; 99: 9–11.CrossRefGoogle Scholar
18. Nemeth, A, Krause, S, Blank, D, et al. Isolation of genomic and cDNA clones encoding bovine poly(A) binding protein II. Nuclei Acid Res 1995; 23: 4034–4041.CrossRefGoogle ScholarPubMed
19. Sherman, MY, Goldberg, AL. Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 2001; 29: 15–32.CrossRefGoogle ScholarPubMed
20. Bates, GP, Mangiarini, L, Davies, SW. Transgenic mice in the study of polyglutamine repeat expansion diseases. Brain Pathol 1998; 8: 699–714.CrossRefGoogle Scholar
21. Forood, B, Perez-Paya, E, Houghten, RA, Blondelle, SE. Formation of an extremely stable polyalanine beta-sheet macromolecule. Biochem Biophys Res Commun 1995; 211: 7–13.CrossRefGoogle ScholarPubMed
22. Wahle, E. A novel poly(A)-binding protein acts as a specificity factor in the second phase of messenger RNA polyadenylation. Cell 1991; 66: 759–768.CrossRefGoogle ScholarPubMed
23. Colgan, DF, Manley, JL. Mechanism and regulation of mRNA polyadenylation. Genes Dev 1997; 11: 2755–2766.CrossRefGoogle ScholarPubMed
24. Prueitt, RL, Zinn, AR. A fork in the road to fertility. Nat Genet 2001; 27: 132–134.CrossRefGoogle ScholarPubMed
25. Rankin, J, Wyttenbach, A, Rubinsztein, DC. Intracellular green fluorescent protein-polyalanine aggregates are associated with cell death. Biochem J 2000; 348: 15–19.CrossRefGoogle ScholarPubMed
26. Lau, PP, Xiong, W, Zhu, HJ, et al. Apolipoprotein B mRNA editing is an intranuclear event that occurs posttranscriptionally coincident with splicing and polyadenylation. J Biol Chem 1991; 266: 20550–20554.CrossRefGoogle ScholarPubMed
27. Turmaine, M, Raza, A, Mahal, A, et al. Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington’s disease. Proc Natl Acad Sci USA 2000; 97: 8089–8097.CrossRefGoogle Scholar
28. Calado, A, Kutay, U, Kuhn, U, et al. Deciphering the cellular pathway for transport of poly(A)-binding protein II. RNA 2000; 6: 245–256.CrossRefGoogle ScholarPubMed
29. Swanson, MS. Functions of nuclear pre-mRNA/mRNA binding proteins. In: Lamond, AI, Eds. Pre-mRNA Processing. Berlin/New York: Springer Verlag, 1995: 17–33.Google Scholar
30. Nagai, T, Aruga, J, Takada, S, et al. The expressions of the mouse Zic1, Zic2, and Zic3 genes suggest an essential role for Zic genes in body pattern formation. Dev Biol 1997; 182: 299–313.CrossRefGoogle ScholarPubMed
31. Goodman, FR, Mundlos, S, Muragaki, Y, et al. Synpolydactyly phenotypes correlated with size of expansions in HOXD13 polyalanine tract. Proc Natl Acad Sci USA 1997; 94: 7458–7463.CrossRefGoogle ScholarPubMed
32. Mundlos, S, Olsen, BR. Heritable diseases of the skeleton. Part II: molecular insights into skeletal development-matrix components and their homeostasis . FASEB J 1997; 11: 227–233.CrossRefGoogle ScholarPubMed
33. Otto, F, Thornell, AP, Crompton, T, et al. Cbfa1, a candidate gene for Cleidocranial Dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997; 89: 765–771.Google ScholarPubMed
34. Blumen, SC, Sadeh, M, Korczyn, AD, et al. Intranuclear inclusions in oculopharyngeal muscular dystrophy among Bukhara Jews. Neurol 1996; 46: 1324–1328.CrossRefGoogle ScholarPubMed
35. Teh, BT, Sullivan, AA, Farnebo, F, et al. Oculopharyngeal muscular dystrophy (OPMD)-report and genetic studies of an Australian kindred. Clin Genet 1997; 51: 52–55.CrossRefGoogle ScholarPubMed
36. Zlotogora, J, Sagi, M, Cohen, T. The blepharophimosis, ptosis, and epicanthus inversus syndrome: delineation of two types. Am J Hum Genet 1983; 35: 1020–1027.Google ScholarPubMed
37. Porschke, H, Kress, W, Reichmann, H, et al. Oculopharyngeal muscular dystrophy in a northern German family linked to chromosome 14q, and presenting carnitine deficiency. Neuromuscul Disord 1997; 7(Suppl 1): S57–S62.CrossRefGoogle Scholar
38. Crisponi, L, Deiana, M, Loi, A, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 2001; 27: 159–166.CrossRefGoogle ScholarPubMed
39. Lau, PP, Zhu, HJ, Nakamuta, M, Chan, L. Cloning of an apobec-1-binding protein that also interacts with apolipoprotein B mRNA and evidence for its involvement in RNA editing. J Biol Chem 1997; 272: 1452–1455.CrossRefGoogle ScholarPubMed
40. Brais, B, Bouchard, JP, Xie, YG, et al. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 1998; 18: 164–167.CrossRefGoogle ScholarPubMed
41. Gaspar, C, Jannatipour, M, Dion, P, et al. CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation. Hum Mol Genet 2000; 9: 1957–1966.CrossRefGoogle ScholarPubMed
42. Dahl, R, Wani, B, Hayman, MJ. The Ski oncoprotein interacts with Skip, the human homolog of Drosopila Bx42. Oncogene 1998; 16: 1579–1586.Google Scholar
43. Wahle, E. Poly(A) tail length control is caused by termination of processive synthesis. J Biol Chem 1995; 270: 2800–2808.CrossRefGoogle ScholarPubMed
44. Fan, X, Dion, P, Laganiere, J, et al. Oligomerization of polyalanine expanded PABPN1 facilitates nuclear protein aggregation that is associated with cell death. Hum Mol Genet 2001; 10: 2341–2351.CrossRefGoogle ScholarPubMed
45. Temtamy, SA, McKusick, VA. Syndactyly as an isolated malformation. In: The Genetics of Hand Malformations. Birth Defects: Original Article Series vol. XIV (3). Alan RL. New York, 1978; 301–322.Google ScholarPubMed
46. Muragaki, Y, Mundlos, S, Upton, J, Olsen, BR. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science 1996; 272: 548–551.CrossRefGoogle ScholarPubMed
47. Brunet, G, Tome, FM, Samson, F, et al. Dytrophie musculaire oculopharyngee. Recensement des familles francaises et etude genealogique. Rev Neurol 1990; 146: 425–429.Google Scholar
48. Mundlos, S, Olsen, BR. Heritable diseases of the skeleton. Part I: molecular insights into skeletal development-transcription factors and signaling pathways . FASEB J 1997; 11: 125–132.CrossRefGoogle ScholarPubMed
49. Izpisua-Belmonte, JC, Duboule, D. Homeobox genes and pattern formation in the vertebrate limb. Dev Biol 1992; 152: 26–36.CrossRefGoogle ScholarPubMed
50. Brais, B, Rouleau, GA, Bouchard, JP, et al. Oculopharyngeal muscular dystrophy. Semin Neurol 1999; 19: 59–66.CrossRefGoogle ScholarPubMed
51. Tome, FM, Fardeau, M. Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuropathologica 1980; 49: 85–87.Google ScholarPubMed
52. Pratt, MF, Meyers, PK. Oculopharyngeal muscular dystrophy: recent ultrastructural evidence for mitochondrial abnormalities. Laryngoscope 1986; 96: 368–373.Google ScholarPubMed
53. Tome, FM, Askanas, V, Engel, WK, et al. Nuclear inclusions in innervated cultured muscle fibers from patients with oculopharyngeal muscular dystrophy. Neurol 1989; 39: 926–932.CrossRefGoogle ScholarPubMed
54. Halal, F. The hand-foot-genital (hand-foot-uterus) syndrome: family report and update. Am J Med Genet 1988; 30: 793–803.CrossRefGoogle ScholarPubMed
55. Goodman, FR, Bacchelli, C, Brady, AF, et al. Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. Am J Hum Genet 2000; 67: 197–202.Google ScholarPubMed
56. Innerarity, TL, Boren, J, Yamanaka, S, Olofsson, SO. Biosynthesis of apolipoprotein B48-containing lipoproteins. J Biol Chem 1996; 271: 2353–2356.CrossRefGoogle ScholarPubMed
57. Brais, B, Xie, YG, Sanson, M, et al. The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac alpha and beta myosin heavy chain genes on chromosome 14q11.2-q13. Hum Mol Genet 1995; 4: 429–434.CrossRefGoogle Scholar
58. Nanni, L, Croen, LA, Lammer, EJ, Muenke, M. Holoprosencephaly: molecular study of a California population. Am J Med Genet 2000; 90: 315–319.Google ScholarPubMed
59. 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: 393–400.CrossRefGoogle ScholarPubMed
60. Blondelle, SE, Forood, B, Houghten, RA, Perez-Paya, E. Polyalanine-based peptides as models for self-associated beta-pleated-sheet complexes. Biochem 1997; 36: 8393–8400.CrossRefGoogle ScholarPubMed
61. Keller, RW, Kuhn, U, Aragon, M, et al. The nuclear poly(A) binding protein, PABP2, forms an oligomeric particle covering the length of the poly(A) tail. J Mol Biol 2000; 297: 569–583.CrossRefGoogle Scholar
62. Yong, A. Huntington’s Disease and Other Trinucleotide Repeat Disorders. Martin, J, Eds. New York: Scientific American, Inc. 1998.Google Scholar
63. Saudou, F, Finkbeiner, S, Devys, D, Greenberg, ME. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998; 95: 5566.CrossRefGoogle Scholar
64. Klement, IA, Skinner, PJ, Kaytor, MD, et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 1998; 95: 41–53.Google ScholarPubMed
65. Bao, YP, Cook, LJ, O’Donovan, D, et al. Mammalian, yeast, bacterial, and chemical chaperones reduce aggregate formation and death in a cell model of oculopharyngeal muscular dystrophy. J Biol Chem 2002; 277: 12263–12269.CrossRefGoogle Scholar
66. Evert, BO, Wullner, U, Schulz, JB, et al. High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells. Hum Mol Genet 1999; 8: 1169–1176.Google ScholarPubMed
67. Pinol-Roma, S, Dreyfuss, G. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature 1992; 355: 730–732.CrossRefGoogle ScholarPubMed
68. Visa, N, Alzhanova-Ericsson, AT, Sun, X, Kiseleva, E. A pre-mRNA-binding protein accompanies the RNA from the gene through the nuclear pores and into polysomes. Cell 1996; 84: 253–264.CrossRefGoogle ScholarPubMed
69. Nakielny, S, Dreyfuss, G. Nuclear export of proteins and RNAs. Curr Opin Cell Biol 1997; 9: 420–429.Google ScholarPubMed
70. Krecic, AM, Swanson, MS. hnRNP complexes: composition, structure, and function. Curr Opin Cell Biol 1999; 11: 363–371.Google ScholarPubMed
71. Jones, KL. Smith’s Recognizable Patterns of Human Malformation, 5th ed. 1997 Philadelphia: W.B. Saunders Company.Google Scholar