Trinucleotide repeat expansion and human disease

Hummerich, Holger; Lehrach, Hans

doi:10.1002/elps.11501601282

Cited by 14 publications

(8 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The NMR study of a single U⅐U mismatch within an asymmetrical, biologically relevant context also showed that the mismatch is base-paired (36). It forms the NH-3-O-4 hy- 5 , in all hairpin loops, and in the stem of (CUG) 11 ; structure 2, distribution of cleavages in the stems of (CUG) 21 and (CUG) 49 at 20°C; structure 3, pattern observed in the stems of (CUG) 21 drogen bond, which forces one of the two U nucleotides to adopt an extended trans-conformation of the backbone to accommodate the mismatch.…”

Section: Discussionmentioning

confidence: 99%

“…(CUG) 5 and Flanking Sequences Are Single-stranded-The repeat region of (CUG) 5 is cleaved by lead ions with the order The reaction conditions were the same as specified in the legend to Fig. 1.…”

Section: Rna Models and Structure Probes-mentioning

confidence: 99%

“…of reactivity CpU Ͼ UpG Ͼ GpC, which is characteristic for the single-stranded looped repeats in all hairpin-forming repeats analyzed here and for stem cuts in the least stable hairpin, (CUG) 11 . In sequences flanking the (CUG) 5 repeat, all G nucleotides are good targets for T 1 ribonuclease, and only a few sites are resistant to both S 1 nuclease and lead ions (Fig. 5).…”

Section: Rna Models and Structure Probes-mentioning

confidence: 99%

“…The latter effect indicates a relaxed metastable structure of the stem. (CUG) 5 repeats do not form any detectable secondary structure, whereas hairpins of increasing stability are formed by (CUG) 11 , (CUG) 21 , and (CUG) 49 . The potential role of the RNA hairpin structure in the pathogenesis of myotonic dystrophy is discussed.…”

mentioning

confidence: 99%

“…The progress of research in this new area has been discussed in several recent reviews (1)(2)(3)(4)(5). One of these diseases is myotonic dystrophy (dystrophia myotonica (DM)), 1 the most prevalent form of muscular dystrophy in adults with a global incidence of 1 in 8000.…”

mentioning

confidence: 99%

See 4 more Smart Citations

CUG Repeats Present in Myotonin Kinase RNA Form Metastable “Slippery” Hairpins

Напиерала

Krzyżosiak

1997

Journal of Biological Chemistry

156

147

View full text Add to dashboard Cite

We show that CUG repeats form "slippery" hairpins in their natural sequence context of the myotonin kinase gene transcript. This novel type of RNA structure is characterized by strong S 1 and T 1 nuclease and lead cleavages in the terminal loop and by mild lead cleavages in the hairpin stem. The latter effect indicates a relaxed metastable structure of the stem. (CUG) 5 repeats do not form any detectable secondary structure, whereas hairpins of increasing stability are formed by (CUG) 11 , (CUG) 21 , and (CUG) 49 . The potential role of the RNA hairpin structure in the pathogenesis of myotonic dystrophy is discussed.Eleven human diseases associated with the expansion of trinucleotide repeats have been identified so far. The progress of research in this new area has been discussed in several recent reviews (1-5). One of these diseases is myotonic dystrophy (dystrophia myotonica (DM)), 1 the most prevalent form of muscular dystrophy in adults with a global incidence of 1 in 8000. The molecular basis of this multisystemic disease, with a complex clinical picture, is the expanded CTG repeat in the myotonic dystrophy protein kinase (DMPK) gene. The repeat expansions, which cause DM, range from 50 repeats in mildly affected patients to Ͼ2000 repeats in the most severe congenital cases (6 -8).Despite the fact that the nature of the underlying DM mutation has been known for the past 6 years, the molecular pathology of this disease is not understood. In particular, it has been difficult to find the molecular mechanism by which this specific mutation, located in the 3Ј-UTR of the DMPK gene, causes the dominantly inherited disease. One of several recent proposals links the inheritance pattern with the molecular effects observed at the RNA level. It takes advantage of the observation that dramatic decreases in both mutant and normal DMPK poly(A) ϩ RNAs, as compared with the primary transcripts, occur in the DM tissue (9). This suggests that the expanded CUG repeat may have a dominant effect either on the processing of both the normal and expanded transcripts or on their transport to the cytoplasm. Other authors observed only a decrease in the expanded poly(A) ϩ transcript (10). The specific (CUG) n -binding proteins, discovered recently (11-13), may be involved in normal DMPK RNA processing, transport, and/or translation. These RNA-protein interactions may be impaired by the expanded DMPK transcript.Understanding the molecular basis of the DM disease is hampered by the lack of knowledge of the RNA structure formed by the CUG repeats. To fill this gap and to provide a background for further studies on the role of RNA level effects in the pathogenesis of myotonic dystrophy, we have analyzed the structure of the repeat region of DMPK RNA. In this paper, we describe the properties of an unusual "slippery" RNA hairpin that contains a metastable stem. The stability of the hairpin increases with the repeat length, and we postulate that long stable hairpins are important factors in DM pathogenesis. MATERIALS AND METHODS DNA Templa...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Rna Models and Structure Probes-mentioning

confidence: 99%

Section: Rna Models and Structure Probes-mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

CUG Repeats Present in Myotonin Kinase RNA Form Metastable “Slippery” Hairpins

Напиерала

Krzyżosiak

1997

Journal of Biological Chemistry

156

147

View full text Add to dashboard Cite

show abstract

Northern blot analysis of simple repetitive sequence transcription in plants

et al. 1996

View full text Add to dashboard Cite

The presence of simple repetitive sequence motifs in RNA from various plant species was probed by Northern blot analysis. Hybridization of total, poly(A)(+)- and poly(A)(-)-RNA with microsatellite-complementary oligonucleotide probes revealed distinct bands with most but not all probe/species combinations, demonstrating the presence of di-, tri- and tetranucleotide repeat motifs in plant transcripts. Only trinucleotide repeat-derived hybridization signals were found to be enriched in the poly(A)(+)-fraction. The quality of Northern blot signals proved to be highly dependent on hybridization stringency. Thus, under the stringency conditions usually applied for oligonucleotide hybridization, some probes [(GT)8, (CAC)5, (TCC)5, and (CCTA)4] cross-hybridized to bands corresponding in size to 18S and/or 26S rRNA. Cross-hybridization to rRNA was significantly reduced at higher stringencies. These results stress the importance of carefully adjusting the hybridization conditions in Northern blot analysis of simple sequence transcripts.

show abstract

Mapping and Characterization of Novel (CAG)nRepeat cDNAs from Adult Human Brain Derived by the Oligo Capture Method

Reddy¹,

Stockburger²,

Gillevet³

et al. 1997

Genomics

View full text Add to dashboard Cite

and FRA11B) associated with mental retardation The expansion of a (CAG) n trinucleotide repeat has (Jones et al., 1994; Knight et al., 1993; been associated with at least eight neurological disor-1991); (CTG) n expansions found in myotonic dystrophy ders in which the repeats code for polyglutamine in (Brook et al., 1992; Fu et al., 1992;Mahadevan et al., the protein. To identify additional genes that possess 1992); and (GAA) n expansions seen in Freidreich ataxia (CAG) n repeats, single-stranded cDNA clones derived (Campuzano et al., 1996). Two additional fragile sites from adult human brain were screened using biotinyl- (FRAXF and FRA16A) are associated with (CGG) n tripated oligonucleotide (CAG) 8 , and the hybridizing com-let repeat expansions but have not been implicated plexes were isolated with strepavidin-coated para-with any human diseases (Nancarrow et al., 1994; Parmagnetic beads. A total of 119 cDNA clones were iso- rish et al., 1994). Dynamic mutations in coding regions lated and initially characterized by end sequencing. involve (CAG) n expansions observed in patients with BLAST homology searches were used to reduce redun-spinal bulbar muscular atrophy (SBMA; La Spada et bropallidoluysian atrophy (DRPLA; Koide et al., 1994; A total of 19 novel cDNAs were further characterized Nagafuchi et al., 1994; which is allelic to Haw River by determining chromosomal assignments using the syndrome; Burke et al., 1994;Potter et al., 1996), MaStanford G3 and Genebridge radiation-reduced hybrid mapping panels. Transcript sizes and tissue expres-chado-Joseph disease (which is allelic to SCA3; Kawasion patterns were determined by Northern blot analy- guchi et al., 1994), and, more recently, SCA2 (Imbert sis. Two of 19 clones showed specific or high expres -et al., 1996) and SCA6 (Zhuchenko et al., 1997). sion in brain. These cDNAs are ideal candidate genesMost of the diseases caused by (CAG) n repeat expanfor other neurodegenerative disorders, such as spino-sions share certain clinical features such as neuronal cerebellar ataxia types 5 and 7, and may also be impli-degeneration, dominant inheritance patterns, and gecated in psychiatric diseases such as bipolar affected netic anticipation, resulting in earlier age of onset in disorder and schizophrenia. ᭧ 1997 Academic Press successive generations largely in part due to the tenKey Words: trinucleotide repeats; CAG expansion; dency of the affected parent's allele to expand in the EST; neurodegeneration; brain expression. germ line, particularly when transmitted from the paternal line

show abstract

Trinucleotide repeat expansion and human disease

Cited by 14 publications

References 81 publications

CUG Repeats Present in Myotonin Kinase RNA Form Metastable “Slippery” Hairpins

CUG Repeats Present in Myotonin Kinase RNA Form Metastable “Slippery” Hairpins

Northern blot analysis of simple repetitive sequence transcription in plants

Mapping and Characterization of Novel (CAG)nRepeat cDNAs from Adult Human Brain Derived by the Oligo Capture Method

Contact Info

Product

Resources

About