Home LiteratureArticle Details
PMID: 9171073 Published · ppublish English Journal Article Review

Trinucleotide repeats associated with human disease.

Nucleic acids research ·Vol. 25 ·No. 12 ·1997-06-15 ·Pages 2245-54

Mitas M

Abstract

Triplet repeat expansion diseases (TREDs) are characterized by the coincidence of disease manifestation with amplification of d(CAG. CTG), d(CGG.CCG) or d(GAA.TTC) repeats contained within specific genes. Amplification of triplet repeats continues in offspring of affected individuals, which generally results in progressive severity of the disease and/or an earlier age of onset, phenomena clinically referred to as 'anticipation'. Recent biophysical and biochemical studies reveal that five of the six [d(CGG)n, d(CCG)n, (CAG)n, d(CTG)n and d(GAA)n] complementary sequences that are associated with human disease form stable hairpin structures. Although the triplet repeat sequences d(GAC)n and d(GTC)n also form hairpins, repeats of the double-stranded forms of these sequences are conspicuously absent from DNA sequence databases and are not anticipated to be associated with human disease. With the exception of d(GAG)n and d(GTG)n, the remaining triplet repeat sequences are unlikely to form hairpin structures at physiological salt and temperature. The details of hairpin structures containing trinucleotide repeats are summarized and discussed with respect to potential mechanisms of triplet repeat expansion and d(CGG.CCG) n methylation/demethylation.

MeSH Terms
Base Sequence DNA/chemistry Genetic Diseases, Inborn/genetics Humans Models, Molecular Nucleic Acid Conformation Trinucleotide Repeats
Chemicals
DNA
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Mitas M
Department of Biochemistry and Molecular Biology, Oklahoma State University, 246 Noble Research Center, Stillwater, OK 74078, USA. mmitas@biochem.okstate.edu
References (89)
89 references, click to expand
  1. Recognition of unusual DNA structures by human DNA (cytosine-5)methyltransferase.
    J Mol Biol. 1991 Jan 5;217(1):39-51 PMID: 1988679
  2. Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome.
    Cell. 1991 Feb 22;64(4):861-6 PMID: 1997211
  3. 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 May 31;65(5):905-14 PMID: 1710175
  4. Demethylation of CpG islands in embryonic cells.
    Nature. 1991 May 16;351(6323):239-41 PMID: 2041571
  5. Absence of expression of the FMR-1 gene in fragile X syndrome.
    Cell. 1991 Aug 23;66(4):817-22 PMID: 1878973
  6. Methylation patterns of the human apoA-I/C-III/A-IV gene cluster in adult and embryonic tissues suggest dynamic changes in methylation during development.
    J Biol Chem. 1991 Dec 15;266(35):23676-81 PMID: 1748645
  7. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox.
    Cell. 1991 Dec 20;67(6):1047-58 PMID: 1760838
  8. Metal ions cause the isomerization of certain intramolecular triplexes.
    J Biol Chem. 1992 Jan 15;267(2):1259-64 PMID: 1309767
  9. Cation-dependent transition between the quadruplex and Watson-Crick hairpin forms of d(CGCG3GCG).
    Biochemistry. 1992 Jan 28;31(3):833-41 PMID: 1731941
  10. Recognition of foldback DNA by the human DNA (cytosine-5-)-methyltransferase.
    Biochemistry. 1992 Jan 28;31(3):850-4 PMID: 1731943
  11. 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 Feb 21;68(4):799-808 PMID: 1310900
  12. Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene.
    Science. 1992 Mar 6;255(5049):1253-5 PMID: 1546325
  13. An unstable triplet repeat in a gene related to myotonic muscular dystrophy.
    Science. 1992 Mar 6;255(5049):1256-8 PMID: 1546326
  14. Developmental pattern of gene-specific DNA methylation in the mouse embryo and germ line.
    Genes Dev. 1992 May;6(5):705-14 PMID: 1577268
  15. The essentials of DNA methylation.
    Cell. 1992 Jul 10;70(1):5-8 PMID: 1377983
  16. Unusual DNA conformation at low pH revealed by NMR: parallel-stranded DNA duplex with homo base pairs.
    Biochemistry. 1992 Nov 3;31(43):10510-7 PMID: 1420168
  17. Genetic mapping of a locus predisposing to human colorectal cancer.
    Science. 1993 May 7;260(5109):810-2 PMID: 8484120
  18. DNA methylation represses FMR-1 transcription in fragile X syndrome.
    Hum Mol Genet. 1992 Sep;1(6):397-400 PMID: 1301913
  19. Human strand-specific mismatch repair occurs by a bidirectional mechanism similar to that of the bacterial reaction.
    J Biol Chem. 1993 Jun 5;268(16):11838-44 PMID: 8505312
  20. 5'-CGA sequence is a strong motif for homo base-paired parallel-stranded DNA duplex as revealed by NMR analysis.
    Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5224-8 PMID: 8506370
  21. Crystal structure of the HhaI DNA methyltransferase complexed with S-adenosyl-L-methionine.
    Cell. 1993 Jul 30;74(2):299-307 PMID: 8343957
  22. Demethylation of somatic and testis-specific histone H2A and H2B genes in F9 embryonal carcinoma cells.
    Mol Cell Biol. 1993 Sep;13(9):5538-48 PMID: 8355699
  23. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.
    Cell. 1993 Dec 3;75(5):1027-38 PMID: 8252616
  24. Solution structure of a parallel-stranded G-quadruplex DNA.
    J Mol Biol. 1993 Dec 20;234(4):1171-83 PMID: 8263919
  25. High resolution methylation analysis of the FMR1 gene trinucleotide repeat region in fragile X syndrome.
    Hum Mol Genet. 1993 Oct;2(10):1659-65 PMID: 8268919
  26. On base flipping.
    Cell. 1995 Jul 14;82(1):9-12 PMID: 7606789
  27. The trinucleotide repeat sequence d(GTC)15 adopts a hairpin conformation.
    Nucleic Acids Res. 1995 Jul 25;23(14):2706-14 PMID: 7651831
  28. Expansion and deletion of CTG repeats from human disease genes are determined by the direction of replication in E. coli.
    Nat Genet. 1995 Jun;10(2):213-8 PMID: 7663518
  29. DNA determinants and substrate specificities of Escherichia coli MutY.
    J Biol Chem. 1995 Oct 6;270(40):23582-8 PMID: 7559523
  30. The trinucleotide repeat sequence d(CGG)15 forms a heat-stable hairpin containing Gsyn. Ganti base pairs.
    Biochemistry. 1995 Oct 3;34(39):12803-11 PMID: 7548035
  31. The purine-rich trinucleotide repeat sequences d(CAG)15 and d(GAC)15 form hairpins.
    Nucleic Acids Res. 1995 Oct 25;23(20):4055-7 PMID: 7479064
  32. CGG repeats associated with DNA instability and chromosome fragility form structures that block DNA synthesis in vitro.
    Nucleic Acids Res. 1995 Oct 25;23(20):4202-9 PMID: 7479085
  33. Mismatch repair in Escherichia coli enhances instability of (CTG)n triplet repeats from human hereditary diseases.
    Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11019-23 PMID: 7479928
  34. DNA CTG triplet repeats involved in dynamic mutations of neurologically related gene sequences form stable duplexes.
    Nucleic Acids Res. 1995 Nov 11;23(21):4303-11 PMID: 7501450
  35. Microsatellite instability and other molecular abnormalities in human prostate cancer.
    Jpn J Cancer Res. 1995 Oct;86(10):956-61 PMID: 7493915
  36. Solution structure of a DNA quadruplex containing the fragile X syndrome triplet repeat.
    J Mol Biol. 1995 Dec 8;254(4):638-56 PMID: 7500339
  37. hMSH2-independent DNA mismatch recognition by human proteins.
    J Biol Chem. 1996 Jan 19;271(3):1789-96 PMID: 8576184
  38. CTG triplet repeats from human hereditary diseases are dominant genetic expansion products in Escherichia coli.
    J Biol Chem. 1996 Jan 26;271(4):1853-6 PMID: 8567629
  39. The expanding world of trinucleotide repeats.
    Science. 1996 Mar 8;271(5254):1374-5 PMID: 8596908
  40. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.
    Science. 1996 Mar 8;271(5254):1423-7 PMID: 8596916
  41. Structure and dynamics of the DNA hairpins formed by tandemly repeated CTG triplets associated with myotonic dystrophy.
    Nucleic Acids Res. 1996 Feb 15;24(4):775-83 PMID: 8604323
  42. Solution structures of the individual single strands of the fragile X DNA triplets (GCC)n.(GGC)n.
    Nucleic Acids Res. 1996 Feb 15;24(4):784-92 PMID: 8604324
  43. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13.
    Science. 1996 Apr 26;272(5261):548-51 PMID: 8614804
  44. CTG triplet repeats from the myotonic dystrophy gene are expanded in Escherichia coli distal to the replication origin as a single large event.
    J Mol Biol. 1996 May 17;258(4):543-7 PMID: 8636989
  45. Stability of intrastrand hairpin structures formed by the CAG/CTG class of DNA triplet repeats associated with neurological diseases.
    Nucleic Acids Res. 1996 Jun 1;24(11):1992-8 PMID: 8668527
  46. Alternative structures in duplex DNA formed within the trinucleotide repeats of the myotonic dystrophy and fragile X loci.
    Biochemistry. 1996 Apr 16;35(15):5041-53 PMID: 8664297
  47. DNA demethylation in vitro: involvement of RNA.
    Cell. 1996 Sep 6;86(5):709-18 PMID: 8797818
  48. Trinucleotide repeat expansion and human disease.
    Annu Rev Genet. 1995;29:703-28 PMID: 8825491
  49. Genetically unstable CXG repeats are structurally dynamic and have a high propensity for folding. An NMR and UV spectroscopic study.
    J Mol Biol. 1996 Nov 29;264(2):323-36 PMID: 8951379
  50. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel.
    Nat Genet. 1997 Jan;15(1):62-9 PMID: 8988170
  51. Trinucleotide repeat disorders in humans: discussions of mechanisms and medical issues.
    FASEB J. 1996 Dec;10(14):1589-97 PMID: 9002550
  52. Dynamics of demethylation and activation of the alpha-actin gene in myoblasts.
    Cell. 1990 Dec 21;63(6):1229-37 PMID: 2261641
  53. Mutation of a mutL homolog in hereditary colon cancer.
    Science. 1994 Mar 18;263(5153):1625-9 PMID: 8128251
  54. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer.
    Nature. 1994 Mar 17;368(6468):258-61 PMID: 8145827
  55. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation.
    Nat Genet. 1994 Mar;6(3):273-81 PMID: 8012390
  56. Distribution of trinucleotide microsatellites in different categories of mammalian genomic sequence: implications for human genetic diseases.
    Genomics. 1994 May 1;21(1):116-21 PMID: 8088779
  57. A mismatch recognition defect in colon carcinoma confers DNA microsatellite instability and a mutator phenotype.
    Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8905-9 PMID: 8090742
  58. Hypermethylation of telomere-like foldbacks at codon 12 of the human c-Ha-ras gene and the trinucleotide repeat of the FMR-1 gene of fragile X.
    J Mol Biol. 1994 Oct 21;243(2):143-51 PMID: 7932745
  59. Binding of mismatched microsatellite DNA sequences by the human MSH2 protein.
    Science. 1994 Nov 25;266(5189):1403-5 PMID: 7973733
  60. Mismatch repair, genetic stability, and cancer.
    Science. 1994 Dec 23;266(5193):1959-60 PMID: 7801122
  61. Biological implications of the mechanism of action of human DNA (cytosine-5)methyltransferase.
    Prog Nucleic Acid Res Mol Biol. 1994;49:65-111 PMID: 7863011
  62. Solution structure of two mismatches A.A and T.T in the K-ras gene context by nuclear magnetic resonance and molecular dynamics.
    Eur J Biochem. 1995 Mar 1;228(2):279-90 PMID: 7705340
  63. Hairpin properties of single-stranded DNA containing a GC-rich triplet repeat: (CTG)15.
    Nucleic Acids Res. 1995 Mar 25;23(6):1050-9 PMID: 7731793
  64. Simple tandem DNA repeats and human genetic disease.
    Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3636-41 PMID: 7731957
  65. HhaI and HpaII DNA methyltransferases bind DNA mismatches, methylate uracil and block DNA repair.
    Nucleic Acids Res. 1995 Apr 25;23(8):1380-7 PMID: 7753629
  66. M.HhaI binds tightly to substrates containing mismatches at the target base.
    Nucleic Acids Res. 1995 Apr 25;23(8):1388-95 PMID: 7753630
  67. Trinucleotide repeats that expand in human disease form hairpin structures in vitro.
    Cell. 1995 May 19;81(4):533-40 PMID: 7758107
  68. Hairpins are formed by the single DNA strands of the fragile X triplet repeats: structure and biological implications.
    Proc Natl Acad Sci U S A. 1995 May 23;92(11):5199-203 PMID: 7761473
  69. Methylation of slipped duplexes, snapbacks and cruciforms by human DNA(cytosine-5)methyltransferase.
    Nucleic Acids Res. 1995 May 11;23(9):1584-9 PMID: 7784214
  70. Triad-DNA: a model for trinucleotide repeats.
    Nat Genet. 1995 Apr;9(4):339-41 PMID: 7795634
  71. Compact structures of d(CNG)n oligonucleotides in solution and their possible relevance to fragile X and related human genetic diseases.
    Nucleic Acids Res. 1995 Jun 11;23(11):1876-81 PMID: 7596812
  72. The crystal structure of HaeIII methyltransferase convalently complexed to DNA: an extrahelical cytosine and rearranged base pairing.
    Cell. 1995 Jul 14;82(1):143-53 PMID: 7606780
  73. Human chromosomal fragile site FRA16B is an amplified AT-rich minisatellite repeat.
    Cell. 1997 Feb 7;88(3):367-74 PMID: 9039263
  74. At physiological pH, d(CCG)15 forms a hairpin containing protonated cytosines and a distorted helix.
    Biochemistry. 1997 Mar 25;36(12):3687-99 PMID: 9132022
  75. Helix formation by guanylic acid.
    Proc Natl Acad Sci U S A. 1962 Dec 15;48:2013-8 PMID: 13947099
  76. The selective degradation of pyrimidines in nucleic acids by permanganate oxidation.
    Biochem Biophys Res Commun. 1967 Nov 30;29(4):556-61 PMID: 16496535
  77. Methyl-directed repair of DNA base-pair mismatches in vitro.
    Proc Natl Acad Sci U S A. 1983 Aug;80(15):4639-43 PMID: 6308634
  78. Variations in DNA methylation during mouse cell differentiation in vivo and in vitro.
    Proc Natl Acad Sci U S A. 1984 Apr;81(8):2275-9 PMID: 6585800
  79. G . T base-pairs in a DNA helix: the crystal structure of d(G-G-G-G-T-C-C-C).
    J Mol Biol. 1985 Dec 20;186(4):805-14 PMID: 4093986
  80. Replacement of 5-methylcytosine by cytosine: a possible mechanism for transient DNA demethylation during differentiation.
    Proc Natl Acad Sci U S A. 1986 May;83(9):2827-31 PMID: 3458243
  81. Genomic sequencing reveals a positive correlation between the kinetics of strand-specific DNA demethylation of the overlapping estradiol/glucocorticoid-receptor binding sites and the rate of avian vitellogenin mRNA synthesis.
    Proc Natl Acad Sci U S A. 1986 Oct;83(19):7167-71 PMID: 3463957
  82. Structure, dynamics, and thermodynamics of mismatched DNA oligonucleotide duplexes d(CCCAGGG)2 and d(CCCTGGG)2.
    Biochemistry. 1987 Jun 30;26(13):4068-75 PMID: 3651437
  83. Telomeric DNA oligonucleotides form novel intramolecular structures containing guanine-guanine base pairs.
    Cell. 1987 Dec 24;51(6):899-908 PMID: 3690664
  84. Mispair specificity of methyl-directed DNA mismatch correction in vitro.
    J Biol Chem. 1988 May 15;263(14):6829-35 PMID: 2834393
  85. Relationship between transient DNA hypomethylation and erythroid differentiation of murine erythroleukemia cells.
    Proc Natl Acad Sci U S A. 1988 Dec;85(23):9003-6 PMID: 3194403
  86. Monovalent cation-induced structure of telomeric DNA: the G-quartet model.
    Cell. 1989 Dec 1;59(5):871-80 PMID: 2590943
  87. A guide for probing native small nuclear RNA and ribonucleoprotein structures.
    Methods Enzymol. 1989;180:212-27 PMID: 2515419
  88. Strand-specific mismatch correction in nuclear extracts of human and Drosophila melanogaster cell lines.
    Proc Natl Acad Sci U S A. 1990 Aug;87(15):5837-41 PMID: 2116007
  89. Chemical reactivity of potassium permanganate and diethyl pyrocarbonate with B DNA: specific reactivity with short A-tracts.
    Biochemistry. 1990 Jun 26;29(25):6071-81 PMID: 2166574
Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
0305-1048
DOI
10.1093/nar/25.12.2245
Email
mmitas@biochem.okstate.edu
Published
1997-06-15
Pages
2245-54
Language
English
Region
England
NLM ID
0411011
PMCID
PMC146772
Subset
IM
External Links
PubMed source DOI: 10.1093/nar/25.12.2245 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2