Myotonic dystrophy: will the real gene pleasestep forward!

Harris, Sarah E.; Moncrieff, Colin L.; Johnson, Keith

doi:10.1093/hmg/5.supplement_1.1417

Cited by 74 publications

(44 citation statements)

References 58 publications

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“…1), and it has been suggested that these genes may be involved in the etiology of DM (12). Under a field-effect model for DM, expansion of the triplet would cause an alteration in level of expression from several surrounding genes (11,13,18), possibly because of gross distortions in chromatin structure. To test this hypothesis we have analyzed the levels of expression from DMPK compared with those from DMAHP and 59, the two genes that immediately flank DMPK.…”

Section: Resultsmentioning

confidence: 99%

“…It has been suggested that expansion of the CTG repeat may affect the higher-order structure of DNA, thus altering the level of expression of neighboring genes in a field effect (11)(12)(13)18). To investigate this possibility we have examined the level of expression of 59 and DMAHP, the two genes that immediately flank DMPK, in cytoplasmic fractions of DM and control cell lines.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional abnormality in myotonic dystrophy affects DMPK but not neighboring genes

Alwazzan

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

132

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Myotonic dystrophy (DM) is caused by the expansion of a trinucleotide repeat, CTG, in the 3 untranslated region of a protein kinase gene, DMPK. We set out to determine what effect this expanded repeat has on RNA processing. The subcellular fractionation of RNA and the separate analysis of DMPK transcripts from each allele reveals that transcripts from expanded DMPK alleles are retained within the nucleus and are absent from the cytoplasm of DM cell lines. The nuclear retention of DMPK transcripts occurs above a critical threshold between 80 and 400 CTGs. Further analysis of the nuclear RNA reveals an apparent reduction in the proportion of expansion-derived DMPK transcripts after poly(A) ؉ selection. Quantitative analysis of RNA also indicates that although the level of cytoplasmic DMPK transcript is altered in DM patients, the levels of transcripts from 59 and DMAHP, two genes that immediately f lank DMPK, are unaffected in DM cell lines.Myotonic dystrophy (DM) is the most common form of muscular dystrophy affecting adults. It is dominantly inherited and involves many systems, including endocrine, heart, and brain, though principally it is a disease of muscle characterized by myotonia with muscle weakness and wasting (1). DM is associated with the expansion of a CTG repeat located in the 3Ј untranslated region (UTR) of a protein kinase gene, DMPK (2-4) (See Fig. 1). It is not known how this mutation, in a noncoding part of the gene, exerts an effect at the cellular level, and conf licting data have been published about the effect of repeat expansion on DMPK RNA levels in DM tissues and cell lines (5-8). Three models have been proposed to explain the molecular mechanism of DM (9). First, the mutation may directly effect the level of DMPK protein. Second, the mutation may affect the higherorder structure of DNA around the repeat, altering the level of expression of neighboring genes in a field effect (10 -13). Third, the repeat expansion may produce a gain-of-function mutation at either the DNA or RNA level. Recently, foci of DMPK transcripts containing expanded repeats have been reported in the nuclei of DM muscle specimens and fibroblast cell lines (14), and other studies have suggested that a disruption of RNA processing may be critical for the development of DM (15,16). In view of these findings, we have performed a series of experiments to compare the distribution of expanded and wild-type DMPK alleles in RNA from nuclear and cytoplasmic fractions of DM cells. We have also examined the expression of genes 59 (10, 17) and DMAHP (12), which f lank DMPK, to establish whether this is affected by repeat expansion.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transcriptional abnormality in myotonic dystrophy affects DMPK but not neighboring genes

Alwazzan

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

132

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“…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.…”

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confidence: 99%

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

Напиерала

Krzyżosiak

1997

Journal of Biological Chemistry

156

147

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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...

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“…However, the finding that cataract carriers transmit the DMPK protomutation, and maintain the DM1 mutation in a population, does not exclude the hypothesis that specific multiple polymorphisms nearby predispose to the generation of DM1 mutations (Boucher al 1995;Krahe et al 1995aKrahe et al , 1995bKrahe et al , 1995cHarris et al 1996), or that other mechanisms such as meiotic drive might be involved in the maintenance of the mutation.…”

Section: Discussionmentioning

confidence: 99%

Patients with primary cataract as a genetic pool of DMPK protomutation

et al. 2006

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Myotonic dystrophy 1 (DM1) is known to diminish reproductive fitness in its severe form. Since no de novo mutations are known for this disease, it has the tendency to becomeextinct from a population. To explain the preservation of DM1 in a population, a hypothesis that a pool of subjects for the mutated gene exists in the apparently healthy (non-DM1) population was tested. In order to determine the (CTG) repeat number, PCR was performed in 274 patients found to have primary cataract of adult onset who showed no DM1 symptoms, and were not related to DM1 patients. In four cataract patients (1.46%; 95% CI 0.5-3.7), a protomutation in the myotonin protein kinase gene was found which might lead to a complete mutation after transmission through the next generations. The number of (CTG) repeats in the remaining 270 cataract patients did not differ significantly from the control subjects in terms of the distribution of larger [(CTG)n ‡ 19] versus smaller [(CTG)n < 19] alleles. We consider the primary cataract patients to be the pool of DMPK protomutation from which DM1 mutation is maintained in the population.

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Myotonic dystrophy: will the real gene pleasestep forward!

Cited by 74 publications

References 58 publications

Transcriptional abnormality in myotonic dystrophy affects DMPK but not neighboring genes

Transcriptional abnormality in myotonic dystrophy affects DMPK but not neighboring genes

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

Patients with primary cataract as a genetic pool of DMPK protomutation

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