The complex pathology of trinucleotide repeats

Current Opinion in Cell Biology

Volumn 9, Issue 3, 1997, Pages 364-372

  Reddy, P Sanjeeva ^a,b   Housman, David E ^a  

^a CELERA   (United States)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLUTAMINE; RNA BINDING PROTEIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; CEREBELLAR ATAXIA; CYTOLOGY; DENTATORUBROPALLIDOLUYSIAN ATROPHY; DISEASE TRANSMISSION; DNA STRUCTURE; FRAGILE X SYNDROME; FRIEDREICH ATAXIA; HEREDITARY SPINAL MUSCULAR ATROPHY; HUMAN; HUMAN CELL; HUNTINGTON CHOREA; INTRON; MYOTONIC DYSTROPHY; NONHUMAN; OPEN READING FRAME; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SPINOCEREBELLAR DEGENERATION; TRINUCLEOTIDE REPEAT;

ANIMALIA; ATAXIA;

EID: 0030985156     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0955-0674(97)80009-9     Document Type: Article

References (65)

1. The Huntington's Disease Collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993, 72:971-983.
2. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH: Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991, 352:77-79.
3. Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T et al.: Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet 1994, 6:9-13.
4. Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N ef al.: Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet 1994, 6:14-18.
5. Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I et al.: CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 1994, 8:221-228.
6. Orr HT, Chung MY, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LP, Zoghbi HY: Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993, 4:221-226.
7. Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, Weber C, Mandel JL, Cancel G, Abbas N et al.: Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 1996, 14:285-291.
8. Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A et al.: Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 1996, 14:269-276.
9. Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, Wakisaka A, Tashiro K, Ishida Y, Ikeuchi T et al.: Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Gene 1996, 14:277-284.
10. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC: Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 1997, 15:62-69. This paper adds an intriguing new set of findings to the CAG repeat expansion story. Although symptoms of SCA6 are similar to those of the other SCAs, the length of polyglutamine repeat that causes toxicity is considerably shorter than for any of the other type I diseases. As few as 20 in-frame CAG repeats are necessary to cause disease in SCA6. Another intriguing aspect of this paper is that the pathological polyglutamine repeat is found in the coding region of a gene whose function is well understood; it is a voltage-dependent calcium channel.
11. Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T et al.: Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 1992, 68:799-808.
12. Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards DI: Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p (CGG)n. Science 1991, 252:1711-1714.
13. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kühl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP et al.: Identification of a gene (FMR-1 containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991, 65:905-914.
14. Gu Y, Shen Y, Gibbs RA, Nelson DL: Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island. Nat Genet 1996, 13:109-113.
15. Campuzano V, Montermini L, Motto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A et al.: Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996, 271:1423-1427. The most recent addition to the type Il disorders, the Friedreich's ataxia repeat expansion is the first triplet repeat that causes human pathology to be found in an intron. This paper gives a clear and logical exposition of the impact of the GAA repeat expansion on the loss of function of the transcript in which it is embedded.
16. Harper P: Myotonic Dystrophy, edn 2. Philadelphia: Saunders; 1989.
17. Nussbaum RL, Ledbetter DH: Fragile X syndrome: a unique mutation in man. Annu Rev Genet Dev 1986, 20:109-145.
18. Geoffroy G, Barbeau A, Breton G, Lemieux B, Aube M, Leger C, Bouchard JP: Clinical description and roentgenologic evaluation of patients with Friedreich's ataxia. Can J Neurol Sci 1976, 3:279-286.
19. Strong TV, Tagle DA, Valdes JM, Elmer LW, Boehm K, Swaroop M, Kaatz KW, Collins FS, Albin RL: Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues. Nat Genet 1993, 5:259-265.
20. Margolis RL, Li SH, Young WS, Wagster MV, Stine OC, Kidwai AS, Ashworth RG, Ross CA: DRPLA gene (atrophin-1) sequence and mRNA expression in human brain. Brain Res Mol Brain Res 1996, 36:219-226. An example of a study which demonstrates the expression patterns of one of the genes that is responsible for a type I trinucleotide repeat expansion disease, DRPLA. Of significance is the widespread distribution of tissues in which the gene is expressed, despite the very focal areas of neuropathology observed in DRPLA.
21. Brunner HG, Bruggenwirth HT, Nillesen W, Jansen G, Hamel BC, Hoppe RL, De Die CE, Howeler CJ, Van Oost BA, Wieringa B et al.: Influence of sex of the transmitting parent as well as of parental allele size on the CTG expansion in myotonic dystrophy (DM). Am J Hum Genet 1993, 53:1016-1023.
22. Trottier Y, Biancalana V, Mandel JL: Instability of CAG repeats in Huntington's disease: relation to parental transmission and age of onset J Med Genet 1994, 31:377-382.
23. Leeflang EP, Zhang L, Tavare S, Hubert R, Srinidhi J, MacDonald ME, Myers RH, De Young M, Wexler NS, Gusella JF et al.: Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: quantification of the mutation frequency spectrum. Hum Mol Genet 1995, 4:1519-1526. The technology of single sperm analysis allows a clear picture to be drawn of the extent of repeat expansion in Huntington's disease males.
24. Eichler EE, Holden JJ, Popovich BW, Reiss AL, Snow K, Thibodeau SN, Richards CS, Ward PA, Nelson DL: Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet 1994, 8:88-94.
25. ••], provides the first demonstration of repeat expansion in the mouse. Exon 1 of the protein Huntingtin with 140 CAG repeats is introduced into the mouse germline as a transgene. Three key findings emerge. First, repeat expansion is observed during germline transmission of the repeat. Second, somatic instability is also observed, particularly in certain brain regions such as the cerebellum. Third, repeat expansion is directly correlated with the transcription of the transgene.
26. •].
27. •].
28. Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A et al.: Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994, 368:258-261.
29. Strand M, Earley MC, Crouse GF, Petes TD: Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 1995, 92:10418-10421.
30. Jaworski A, Rosche WA, Gellibolian R, Kang S, Shimizu M, Bowater RP, Sinden RR, Wells RD: Mismatch repair in Escherichia coli enhances instability of (CTG)n triplet repeats from human hereditary diseases. Proc Natl Acad Sci USA 1995, 92:11019-11023.
31. Wells RD: Molecular basis of genetic instability of triplet repeats. J Biol Chem 1996, 271:2875-2878. Discusses slippage at the replication fork as a mechanism for producing triplet repeat instability.
32. Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, Saudou F, Weber C, David G, Tora L et al.: Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 1995, 378:403-406. Describes a monoclonal antibody (1C2) which recognizes expanded polyglutamine tracts. This antibody is an invaluable reagent for the study of type I diseases.
33. Trottier Y, Devys D, Imbert G, Saudou F, An I, Lutz Y, Weber C, Agid Y, Hirsch EC, Mandel JL: Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form. Nat Genet 1995, 10:104-110.
34. Persichetti F, Ambrose CM, Ge P, McNeil SM, Srinidhi J, Anderson MA, Jenkins B, Barnes GT, Duyao MP, Kanaley L et al.: Normal and expanded Huntington's disease gene alleles produce distinguishable proteins due to translation across the CAG repeat. Mol Med 1995, 1:374-383.
35. Chodak GW, Kranc DM, Puy LA, Takeda H, Johnson K, Chang C: Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate. J Urol 1992, 147:798-803.
36. Servadio A, Koshy B, Armstrong D, Antalffy B, Orr HT, Zoghbi HY: Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nat Genet 1995, 10:94-98.
37. DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel JP, Carraway R, Reeves SA et al.: Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 1995, 14:1075-1081.
38. •].
39. •].
40. •] describe the mouse knockout model for the Huntingtin protein. The consensus of all three papers is that the Huntingtin protein is required during early embryonic development.
41. Perutz MF, Johnson T, Suzuki M, Finch JT: Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci USA 1994, 91:5355-5358.
42. Kahlem P, Terre C, Green H, Djian P: Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: relevance to diseases of the nervous system. Proc Natl Acad Sci USA 1996, 93:14580-14585. This paper extends previous studies suggesting that the pathology of extended polyglutamine repeats may relate to their activity as substrates for transglutaminase.
43. Patterson MN, Hughes IA, Gottlieb B, Pinsky L: The androgen receptor gene mutations database. Nucleic Acids Res 1994, 22:3560-3562.
44. Li XJ, Li SH, Sharp AH, Nucifora F Jr, Schilling G, Lanahan A, Worley P, Snyder SH, Ross CA: A huntingtin-associated protein enriched in brain with implications for pathology. Nature 1995, 378:398-402. Describes the isolation and characterization of a Huntingtin-associated protein, HAP-1. Shows that association of HAP-1 with Huntingtin is dependent upon the length of the polyglutamine segment in Huntingtin.
45. Koshy B, Matilla T, Burright EN, Merry DE, Fischbeck KH, Orr HT, Zoghbi HY: Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase. Hum Mol Genet 1996, 5:1311-1318. Association of the polyglutamine in two type I disease proteins with the enzyme GAPDH is demonstrated.
46. Burright EN, Clark HB, Servadio A, Matilla T, Feddersen RM, Yunis WS, Duvick LA, Zoghbi HY, Orr HT: SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat Cell 1995, 82:937-948. Describes a possible transgenic model for SCA1. When the SCA1 gene with an expanded CAG repeat is overexpressed in Purkinje cells, a neurodegenerative phenotype similar to that of SCA1 is observed.
47. ••]. Overexpression of long tracts of polyglutamines or truncated MJD protein with polyglutamines causes cell death in tissue culture cells.
48. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP: Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 1996, 87:493-506. This is a seminal study in which a series of transgenic mouse lines has been produced. In these mice, Huntingtin exon 1 with approximately 140 CAG triplets is expressed under the control of its own promoter. A neurological phenotype with features common with Huntington's disease is observed. The age of onset of neurological phenotypes in each transgenic line is related to the expression level of the transgene.
49. Siomi H, Siomi MC, Nussbaum RL, Dreyfuss G: The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell 1993, 74:291-298.
50. Ashley C Jr, Wilkinson KD, Reines D, Warren ST: FMR1 protein: conserved RNP family domains and selective RNA binding. Science 1993, 262:563-566.
51. Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL: Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 1991, 66:817-822.
52. Wang YH, Griffith J: Methylation of expanded CCG triplet repeat DNA from fragile X syndrome patients enhances nucleosome exclusion. J Biol Chem 1996, 271:22937-22940. Shows that long repeats of methylated CGG decrease the efficiency of nucleosome assembly. Provides an explanation for the previous observations that methylation of expanded CGG repeats inhibits the expression of the FMR1 gene.
53. Sutcliffe JS, Nelson DL, Zhang F, Pieretti M, Caskey CT, Saxe D, Warren ST: DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet 1992, 1:397-400.
54. Siomi MC, Zhang Y, Siomi H, Dreyfuss G: Specific sequences in the fragile X syndrome protein FMR1 and the FXR proteins mediate their binding to 60S ribosomal subunits and the interactions among them. Mol Cell Biol 1996, 16:3825-3832. Demonstrates the interaction of the FMR1 and FXR1 proteins with the 60S ribosomal subunit. Delineates the region of FMR1 that is involved in the interaction, and suggests that FMR1 affects translation or mRNA stability.
55. Wang YH, Griffith J: Expanded CTG triplet blocks from the myotonic dystrophy gene create the strongest known natural nucleosome positioning elements. Genomics 1995, 25:570-573.
56. Lugenbeel K, Peier A, Carson N, Chudley A, Nelson D: Intragenic loss of function mutations demonstrate the primary role of FMR1 in fragile X syndrome. Nat Genet 1995, 10:483-485. Describes the mutations in some FMR patients who do not show CGG repeat expansion. Provides clear evidence for the loss of function of FMR1 in fragile X syndrome patients (see also [57]).
57. De Boulle K, Verkerk AJ, Reyniers E, Vits L, Hendrickx J, Van Roy B, Van den Bos F, De Graaff E, Oostra BA, Willems PJ: A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet 1993, 3:31-35.
58. Fu YH, Friedman DL, Richards S, Pearlman JA, Gibbs RA, Pizzuti A, Ashizawa T, Perryman MB, Scarlato G, Fenwick R Jr et al.: Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. Science 1993, 260:235-238.
59. Sabouri LA, Mahadevan MS, Narang M, Lee DS, Surh LC, Komeluk RG: Effect of the myotonic dystrophy (DM) mutation on mRNA levels of the DM gene. Nat Genet 1993, 4:233-238.
60. Taneja KL, McCurrach M, Schalling M, Housman D, Singer RH: Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol 1995, 128:995-1002.
61. Timchenko LT, Miller JW, Timchenko NA, DeVore DR, Datar KV, Lin L, Roberts R, Caskey CT, Swanson MS: Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. Nucleic Acids Res 1996, 24:4407-4414. Describes the isolation and characterization of two CUG-binding proteins, CUG-BP1 and CUG-BP2. CUG-BP2, a nuclear protein which is associated with the heterogeneous nuclear ribonuclear protein hNab50, shows increased levels in DM cells compared with in normal cells.
62. •]}.
63. Jansen G, Groenen PJ, Bachner D, Jap PH, Coerwinkel M, Oerlemans F, Van den Broek W, Gohlsch B, Pette D, Plomp JJ et al.: Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice. Nat Genet 1996, 13:316-324. In this paper, the authors describe two mouse models - knockout and transgenic. The DMPK null mice showed some myopathy and those with overexpression of DMPK showed hypertophic cardiomyopathy and higher frequency of neonatal mortality (see also [62•]).
64. Boucher CA, King SK, Carey N, Krahe R, Winchester CL, Rahman S, Creavin T, Meghji P, Bailey ME, Chartier FL et al.: A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat Hum Mol Genet 1995, 4:1919-1925.
65. Carvajal JJ, Pook MA, Dos Santos M, Doudney K, Hillermann R, Minogue S, Williamson R, Hsuan JJ, Chamberlain S: The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4-phosphate 5-kinase. Nat Genet 1996, 14:157-162. The authors provide some evidence that the X25 gene which contains the pathological GAA repeat within an intron could be part of an adjacent gene, STM7, which encodes a protein with phoshatidylinositol-4-phosphate 5-kinase activity. The paper raises some interesting issues, such as whether the X25 is truly part of STM7 and, if so, how a defect in phosphoinositide pathway can lead to Friedreich's ataxia.