DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression

Margolis, Jamie M.; Schöser, Benedikt; Moseley, Melinda L.; Day, John W.; Ranum, Laura P.W.

doi:10.1093/hmg/ddl103

Cited by 103 publications

(99 citation statements)

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“…The RNA gain-of-function mechanism initially described in DM1, 18,20,35 wherein repeat expansions are found to be toxic only at the RNA level, now also explains some aspects of pathogenesis in other non-coding expansion disorders, including FXTAS, SCA8, SCA31, HDL2 as well as SCA10 and DM2. 11,[13][14][15][16][17] SCA8 is a unique among these diseases because…”

Section: Mechanisms Of Pathogenesis In Microsatellites Diseasesmentioning

confidence: 99%

“…Intronic (CCTG) n and (ATTCT) n repeat mutations are properly spliced out of the mutant transcripts but are resistant to degradation. 16,65 In DM2 cells, expanded CCUG repeat RNA is the only part of intron 1 from the ZNF9 gene that is retained in the nucleus within MBNL1-positive punctate aggregates. This effect in turn triggers splicing defects similar to those seen in DM1.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

“…The involvement of other repeat-harboring transcripts in neurodegeneration via an RNA gain-of-function mechanism has been described not only for trinucleotide repeat disorders, such as FXTAS, SCA8 and HDL2, [13][14][15] but also for DM2, SCA10 and SCA31. 9,11,16,17 In the RNA gain-of-function mechanism, the expanded repeat of a flawed RNA exerts its toxic function by sequestration and subsequent loss-of-function of RNA binding proteins, such as the muscleblind-like (MBNL) family. Resultant ribonucleoprotein complexes become trapped in the nucleus where they form microscopic bodies and become toxic.…”

Section: Introductionmentioning

confidence: 99%

“…Punctate intranuclear foci that label with antibodies against muscleblind 1 (MBNL1) protein are a characteristic feature of cells expressing non-coding expansions of CUG, 14,[18][19][20] CGG or CCUG repeats. 13,16 More recently, transcripts harboring translated CAG repeat expansions have been observed to form intranuclear MBNL1-positive RNA foci in human HD fibroblasts. 21 This result is in agreement with earlier reports describing nuclear titration of muscleblind 1 protein by exogenous CAG repeat expansions expressed in COSM6 cells, 22 by SCA3 RNA mutation in Drosophila 23 and by untranslated CAG expansion in transgenic Caenorhabditis elegans 24 and transgenic mice.…”

Section: Introductionmentioning

confidence: 99%

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CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders

Wojciechowska

Krzyżosiak

2011

RNA Biology

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Section: Mechanisms Of Pathogenesis In Microsatellites Diseasesmentioning

confidence: 99%

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders

Wojciechowska

Krzyżosiak

2011

RNA Biology

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“…22 ). The RNA foci in DM2 contain only the (CCUG) n RNA 23 , whereas in DM1 the entire processed mutant DMPK mRNA is present 3,4 , suggesting that the context in which the (CUG) repeats reside (that is, the DMPK 3′ UTR) is important with respect to induction of CUG-BP1. Although speculative, this may prove to be important in understanding differences between DM1 and DM2, such as congenital myotonic dystrophy, which is seen only in DM1.…”

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confidence: 99%

Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy

et al. 2006

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Myotonic dystrophy (DM1), the most common muscular dystrophy in adults, is caused by an expanded (CTG) n tract in the 3′ UTR of the gene encoding myotonic dystrophy protein kinase (DMPK) 1 , which results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNAbinding proteins (such as MBNL1) in ribonuclear inclusions 2 . It is unclear if therapy aimed at eliminating the toxin would be beneficial. To address this, we generated transgenic mice expressing the DMPK 3′ UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). We were surprised to find that mice overexpressing a normal DMPK 3′ UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusions. However, we observed increased levels of CUG-binding protein (CUG-BP1) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules.Common features of adult-onset DM1 include myotonia, progressive skeletal muscle loss, cardiac conduction defects, smooth muscle dysfunction, cataracts and insulin resistance 2 . The normal number of CTG repeats (n = 5 to ~30) is higher (n = 50 to >3,000) in individuals with DM1 (ref. 1 ). Unlike the wild-type transcript, mutant DMPK mRNA forms nuclear aggregates 3,4 and is thought to trigger dominant effects by aberrant interactions with or altered activity of RNA splicing factors, principally members of the muscleblind-like (MBNL) family (such as MBNL1) and the CUG-BP and ETR3-like factor (CELF) family (such as CUG-BP1), leading to abnormal splicing of specific RNAs such as chloride channel (Clcn1), insulin Correspondence should be addressed to M.S.M. (mahadevan@virginia.edu). 4 These authors contributed equally to this work. AUTHOR CONTRIBUTIONSM.S.M., R.S.Y., Q.Y., C.D.F.-M., T.D.B. and L.H.P. performed experimental work and data analysis. S.B. generated the transgene constructs. M.S.M. was responsible for conceptual design and execution. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. One potential therapeutic approach in DM1 is to get rid of the toxic RNA from cells. However, it is unclear if this will alleviate the effects of the disease. We used the tetracycline (Tet) inducible system with the reverse tetracycline transactivator (rtTA) to generate double transgenic mice harboring (i) a Tet-responsive, DMPK promoter 10,11 -driven transgene (named GFP-DMPK 3′ UTR) expressing the DMPK 3′ UTR mRNA as part of a GFP transcript, and (ii) a constitutively expressed rtTA transgene (Fig. 1a) Fig. 1). Notably, RNA blots of skeletal muscle RNA showed two major species due to alternative use of polyadenylation signal...

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Molecular Genetic Basis of Myotonic Dystrophy

Radvánszky

Kádaši

2013

Encyclopedia of Life Sciences

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Myotonic dystrophy (DM) comprises at least two genetically distinct forms, both of which are caused by expansions of microsatellite repeats. Expansion of a CTG repeat in the DMPK gene leads to DM1, whereas expansion of a CCTG repeat in the ZNF9 gene causes DM2. In both cases, the repeat units may expand to several thousand repeats. Strikingly similar phenotypes, mutation types and pathological findings suggest a common pathogenic mechanism for both DM1 and DM2. However, the differences between DM1 and DM2 may be a consequence of locus‐specific effects involving haploinsufficiency of different genes and downstream events triggered by CUG or CCUG transcripts. Altogether, the complex DM1 and DM2 phenotypes are probably caused by specific combinations of several possible pathogenic pathways in different tissues of individual patients. Key Concepts: Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are complex multisystemic disorders with highly similar but not identical symptoms. Both DM1 and DM2 are caused by expansions of microsatellite repeats, however, in two distinct genes ( DMPK and ZNF9 ). Mechanisms leading to the DM1 and DM2 symptoms are very complex with several possible pathogenic pathways. The best described pathogenic pathway involves the misregulation of two alternative splicing regulators, CUG‐BP1 (gain of function) and MBNL1 (loss of function), leading to target‐specific splicing alterations. Both CUG‐BP1 and MBNL1 are multifunctional proteins; thus, their activation/sequestration have effect on further cellular functions such as transcription, translation and mRNA decay. Both DM1 and DM2 causing expansions can also lead to decreased levels of proteins coded by genes around and near to the expansion sites, such as DMPK , ZNF9 , SIX5 and DMWD. The exact molecular pathogenic mechanism in certain tissues is probably not uniform, it rather represents a specific combination of several distinct pathogenic pathways.

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DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression

Cited by 103 publications

References 19 publications

CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders

CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders

Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy

Molecular Genetic Basis of Myotonic Dystrophy

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